Cerebellar ataxia


Drug- and toxin-induced cerebellar ataxia: Phenytoin and other anticonvulsants (carbamazepine, barbiturates, gabapentin, benzodiazepines) are well known for their cerebellar toxicity. Other drugs include lithium, cyclosporin, cytotoxic drugs (cytosine arabinoside and 5-fluorouracil). Chronic use or exposure to marijuana, phencyclidine, organic solvents, acrylamide and mercury may also result in cerebellar syndrome. Chronic alcohol intake results either in an acute or subacute cerebellar syndrome typically resulting in lower limb gait ataxia without nystagmus and dysarthria. Brain CT or MRI scan shows typical atrophy of the vermis.

Cerebellar encephalitis: In adults, HIV, HZV, EBV, B. burgerdorfi, syphilis, M. pneumonia, L. pneumophilia are the commonest forms of acute cerebellar ataxia with or without encephalitis. CSF shows mild pleocytosis with normal or elevated protein. Brain MRI is normal. CSF should be tested for genomes of HZV and EBV by PCR. Of particular concern are EBV infections because of their association with lymphoma and nasopharyngeal carcinoma. Similarly, human herpesvirus 8 has been found in primary CNS lymphoma.

Post-infectious syndrome: e.g. Miller-Fisher syndrome.

Hartnup disease: This is an autosomal recessive phenotype involving a transporter for neutral amino acids particularly tryptophan. Occasionally patients will present with late-onset forms of this disease. Episodic attacks of cerebellar ataxia, intermittent red, scaly rash (pellagra-like) over the face, neck, hands, and legs induced by exposure to sunlight, psychosis, emotional instability and transient stupor are the typical clinical manifestation. Occasionally, spasticity, vertigo, nystagmus, ptosis and diplopia are observed. Sunlight exposure, emotional stress, sulfonamides and fasting precipitates the attacks and last for about 2 weeks followed by remission. The diagnosis is based on screening of plasma and urine amino acids (increased levels of neutral aminoaciduria except proline, cystine, ornithine and lysine). The disease is caused by a mutation on chromosome 11q13. High protein diet and nicotinamide 25 mg/day is effective.

Paraneoplastic cerebellar ataxia: The syndrome is characterized by an acute or subacute gait and limb ataxia with vertigo, diplopia, dysphagia, dysarthria, oscillopsia, opsoclonus, myoclonus, sensorineural hearing loss, affected mentation, nystagmus and dysmetria. The rapidity and severity of the cerebellar ataxia together with these non-cerebellar findings are almost pathognomonic for this type of paraneoplastic disorder and help to differentiate from alcoholic and other varieties of cerebellar degeneration. CSF may show transient lymphocytic pleocytosis, normal or elevated protein and mildly elevated IgG synthesis, and oligoclonal bands. 50% of patients with breast and female reproductive tract tumors contain serum and CSF anti-Yo antibodies (anti-purkinje cell antibodies) or less commonly antineuronal (anti-Hu), anti-amphiphysin (breast and small cell lung cancer) or anti-mGluR1 (Hodgkin disease) antibodies. The antibodies may be present two years or more before the associated tumor can be identified. The titer of these antibodies does not predict the course or outcome of the disease or the opposite. Brain MRI findings may be normal in the early stages of the syndrome and later show brainstem and cerebellar atrophy. Prognosis is variable and ranges between 1 to 10 years.

Prion disease: Cerebellar ataxia is a prominent feature of several prion disorders such as CJD, nvCJD and GSS disease. The latter is an autosomal dominant prion disease resulting from a mutation in the prion gene mapped on chromosome 20pter-p12. The onset is usually in the 3rd or 4th decade. Prominent progressive cerebellar ataxia, which occurs before dementia and onset of pyramidal signs. In some families extrapyramidal features, or gaze palsies, deafness, and blindness may predominate. Loss of deep tendon reflexes in the lower limbs with extensor plantar responses frequently develops. Myoclonus however is rare. CSF and neuroimaging may be normal. EEG shows periodic spike and slow wave activity. Survival is usually about 5 years.

Hereditary spinocerebellar ataxia (SCA): SCA formerly called autosomal dominant cerebellar ataxia (ADCA), has a prevalence of 1-5/100,000 in the general population. There is substantial geographical distribution of the different forms of SCA: e.g. SCA-3 is very prominent in Portuguese/Azorean and Dutch families, SCA-2 is common in Cuba, Korea, Italy and India, while SCA-6 is frequently found in German, Dutch and Japanese families. The most common ones are SCA 1-3, 6 and 7. In contrast to autosomal recessive ataxias, SCA almost consistently develop after the age of 25 years. These SCAs share the primary clinical features of cerebellar syndrome with additionally supranuclear ophthalmoplegia, slow eye movements, optic neuropathy, subcortical dementia, extrapyramidal deficits, dysphagia, pyramidal signs, amyotrophy and peripheral neuropathy. On clinical criteria alone, they are often indistinguishable and one patient would fit different categories. The classification of ADCA based on clinical and neuropathologic features was therefore used and divided ADCAs into three different groups (ADCA I-III) based on associated signs. ADCA I: progressive cerebellar gait and limb ataxia with pyramidal and extrapyramidal involvement, slow saccadic eye movements, supranuclear ophthalmoplegia, hyporeflexia and dementia. Onset in 4th decade of life and disease duration of 15 years. SCA-1,2,3 and 4 can be allocated to ADCA I. ADCA II: ataxia with extracerebellar neurologic findings plus retinitis pigmentosa. SCA-7 belongs to this category. ADCA III: predominantly ataxia and frequently late onset with mild pyramidal signs and includes SCA- 6, 8, 10 and 11. The progression is slow, relatively symmetric over 15 years or more. The diagnostic issue can be settled by DNA testing (http://www.geneclinics.org). In patients with SCA 1-3,6 and 7 there is a high number of CAG trinucleotide repeats (>40) with the length of the expanded repeat being inversely correlated with age at onset. Variable degree of cerebellar and brainstem atrophy may be found on neuroimaging. Based on their different chromosomal locations over 25 types of SCA have been identified.

Clinical properties of the SCAs: The most common SCAs are given since for many SCAs (SCA-5,11,12,13,14,16) only a few families have been reported. SCA-1 maps to chromosome 6p22-p23 (ataxin-1). The prevalence of SCA-1 is about 3-15% among ADCAs. Its onset is in the 2nd and 3rd decades. Ataxia is an early and prominent feature along with optic atrophy, dysphagia and pyramidal signs with prominent spasticity. Atrophy and fasciculations may occur late in the facial, lingual and mastication muscles. Loss of vibration, progressive extrapyramidal features and ophthalmoplegia (slow saccades) occur less frequently and are often late manifestations. Axonal sensory or sensorimotor polyneuropathy is found in 42% of patients. There may be some intellectual decline. Brain MRI shows cerebellar and pontine atrophy. CSF is normal. SCA-2 maps to chromosome 12q23-q24.1 (ataxin-2). The prevalence of SCA-2 is about 6-15% among ADCAs. The age of onset is in the 2nd or 3rd decade. The most prominent features are ataxia associated with slow saccades, areflexia and myoclonus. Dystonia and dementia may occur. Lifespan is variably decreased. Axonal sensory or sensorimotor polyneuropathy is found in 80% of SCA-2 patients. SCA-3 or Machado-Joseph disease is the most common SCA, accounting for 30-40% of ADCAs. It maps to chromosome 14q24.3-q32 (> 60-84 CAG repeats). Three clinical types of SCA-3 have been identified: (1) ALS-parkinsonism-dystonia form: onset before the age of 20 years and presents with limb weakness and spasticity affecting predominantly the legs and is associated in the majority of patients with ataxia and extrapyramidal signs (dystonia). Prominent pharyngeal weakness and spasticity with difficulty of speech and swallowing. Horizontal and vertical nystagmus, loss of fast saccadic eye movements and impairment of upward gaze. Peripheral neuropathy may occur. Fasciculations of face and tongue, without atrophy are common and early features. (2) Ataxic type: is the most common form. It begins in the 2nd or 4th decade and consists of progressive cerebellar ataxia followed by pyramidal and extrapyramidal deficits. As in type I, ophthalmoparesis, upward gaze deficits, facial and lingual fasciculations are also present. It needs to be differentiated from OPCA. (3) ataxic-ALS type: or  late onset form (> 50 years) presents with pure cerebellar syndrome, distal sensory loss (all modalities) and distal amyotrophy (axonal sensory or sensorimotor polyneuropathy is found in 54% of the SCA-3 patients). No pyramidal, dementia or extrapyramidal findings occur. Patients are non-ambulatory within 20 years after onset. SCA-4 consists of ataxia with prominent sensory axonal neuropathy and generalized areflexia and pyramidal signs. This form maps to the chromosome 16q22.1. Symptoms start in 2nd to 4th decade. SCA-6 presents with late-onset predominantly pure episodic cerebellar ataxia provoked by stress and fatigue. Downbeat nystagmus is often a pathognomonic sign. Mild vibratory, proprioceptive sensory loss and pyramidal signs can be found. SCA-6 constitutes about 5-15% of ADCAs. It involves a voltage calcium channel subunit and is mapped to chromosome 19p13. MRI shows cerebellar atrophy. Lifespan is normal. The age of onset is in the 4th to 5th decade of life. SCA-7 typically presents with progressive ataxia, upper motor neuron signs (brisk reflexes), macular or retinal degeneration with visual loss, and slow saccades. They often start in childhood. SCA-7 is mapped to chromosome 3p14.1-p21.1. Early onset cases may present with dementia. This form is often misdiagnosed as MS. SCA-7 constitutes about 5% of ADCAs. SCA-8 presenting with mild truncal and limb ataxia, scanning dysarthria, impaired smooth pursuit and horizontal nystagmus, spastic paraparesis and reduced vibration, and is mapped to 13q21. Slowly progressive wheelchair bound in the 4th and 5th decades.

Friedreich ataxia (FA): This form of ataxia is the most common hereditary form (autosomal recessive with variable phenotype) with a frequency of 1/50,000 in the population. Essential diagnostic criteria include its onset before the age of 25 years and <5 years after onset the development of the following: progressive gait ataxia, early areflexia in lower limbs, vibration and joint position sensory deficits, extensor plantar responses, and motor nerve conduction velocity >40 m/s in upper limbs with small or absent SNAPs consistent with axonal sensory neuropathy. Other features are scoliosis, club feet, cardiomyopathy (>50%), diabetes or impaired glucose tolerance (10%) and dementia. Optic neuropathy and deafness occurs in less than 25% of cases. Life expectancy of FA is on average 35 years, death occurring from heart failure. The locus is mapped to chromosome 9q13-q21.1 (frataxin). Frataxin results in intramitochondrial iron accumulation, which explains why FA is now considered a mitochondrial disorder. Abnormal ECG and echocardiography are seen in approximately 60% of cases. CSF is normal. The condition most frequently confused with FA is HSMN I. This demyelinating form of HSMN, is essentially characterized by autosomal dominant inheritance with slow conduction velocities (always <40 m/s). Late-onset FA (after the age of 25 years) (LOFA) is characterized with a slower progression and lower incidence of skeletal deformity. Investigations should include brain MRI, serum vitamin E and B12 levels, and a-fetoprotein levels and DNA analysis to detect GAA trinucleotide expansion.

FA with retained reflexes (FARR) differs from classical FA by pyramidal syndrome in the lower limbs with retained or increased reflexes and spasticity. Although some patients were thought to suffer from EOARR, they were genetically related to the FA locus. Heart disease does not occur in EOARR.

Aceruloplasminemia: This autosomal recessive disorder presents in the 4th - 5th decade of life and is caused by a mutation in the ceruloplasmin gene and affects iron metabolism. A triad of cerebellar ataxia, retinal degeneration and diabetes mellitus in a middle-aged person typically characterizes the disorder. Involuntary movements (late-onset blepharospasm) and dementia may occur in later stages of the disease. Heterozygotes are asymptomatic. Serum ceruloplasmin is low, plasma ferroxidase activity is reduced with 60%, while serum iron and transferrin saturation are normal. Plasma copper and ferritin may be increased. CSF analysis reveals threefold increase in iron concentration. Urinary copper may be increased. Brain MRI shows cerebellar atrophy and T2 weighted studies are remarkable for the presence of iron deposition (increased signal intensity in the basal ganglia and thalamus, and dentate nuclei). PET scan shows cortical glucose hypometabolism.

Familial ataxia with vitamin E deficiency (FAVED): Since its phenotype can be indistinguishable from FA, vitamin E estimation may be essential to make the differential diagnosis. The disease is autosomal recessive begins in adolescence and is caused by a mutation of the a-tocopherol transfer protein (a-TPP gene) on chromosome 8q13.1-3. a-TPP incorporates a-tocopherol into lipoproteins secreted by liver. FAVED results in a progressive spinocerebellar syndrome associated with sensory peripheral neuropathy (loss of vibration sense) with absent tendon reflexes, tremor, dystonia (13%), head titubation (28%), deafness, bladder dysfunction and retinitis pigmentosa. Xanthelasmata and tendon xanthomas may be present. Serum reveals very low vitamin E, high cholesterol, triglyceride levels and β-lipoprotein. Acanthocytes can be found in blood smear. Therapy consists of vitamin E supplements 400-1,200 IU/day for life.

Acquired vitamin E deficiency: Occasionally acquired clinical conditions may cause vitamin E deficiency: intestinal malabsorption syndromes (e.g. short bowel syndrome, intestinal resection, chronic cholestatic liver disease), alcoholism, Whipple disease, hemolytic anemia, renal failure and hemodialysis.

Early onset ataxia with retained reflexes (EOARR): The age of onset is similar to FA but progression is slower. Upper limb reflexes are preserved with lower limb spasticity. Skeletal deformity is mild. Cerebellar atrophy on MRI is inconsistent. The disease is autosomal recessive and carries a better prognosis than FA since cardiomyopathy, diabetes, peripheral neuropathy and optic atrophy rarely occur.

Spastic paraplegia, ataxia, mental retardation (SPAR): This autosomal dominant disorder is characterized by either pure spastic paraplegia, spastic ataxia, spastic ataxia with mental retardation and dystonia. MRI shows cerebellar atrophy. It needs to be differentiated from SCA-1-3, 6-8 and 12, DRPLA and HSP.

Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP): The age of onset may vary from the 1st - 3rd decades of life. This maternally inherited (mitochondrial) disorder presents with the following key features:  ataxia, weakness and axonal sensory neuropathy, mild mental retardation, retinitis pigmentosa and clonic-tonic seizures. A spectrum of neurologic findings may coexist such as migraine, dysarthria, dystonia and pyramidal syndrome. NARP has been associated with obstructive sleep apnea. Serum and CSF lactate and pyruvate levels may be normal or can be slightly increased. Blood citrulline level may be low and has been proposed as surrogate marker for this disorder. Muscle biopsy is normal. Brain MRI findings shows cerebral atrophy, cerebellar atrophy accompanied with dilation of fourth ventricle, and high intensity lesions bilateral in the lenticular nuclei (T2 images). The diagnosis is based on leukocyte mitochondrial DNA analysis which reveals a heteroplasmic point mutation (T8993G) in the ATPase 6 gene of mtDNA. The disorder needs to be differentiated from Refsum disease and Usher syndrome.

Respiratory chain defects (RCDS): These can present in adulthood in a variety of ways: 1) myopathy with exercise intolerance followed by fixed weakness and usually associated with lactic acidosis at rest and exaggerated by exercise (NADH-CoQ reductase or complex I deficiency), 2) myopathy with exercise intolerance with premature fatigue and hyperpnea, often followed by fixed weakness (some forms of FSHMD fit into this category) (complex III deficiency), 3) myopathy with exercise intolerance, myoglobinuria, progressive weakness (defects of mitochondrial protein transport), 4) affecting both muscle and brain; myopathy with exercise intolerance, myoglobinuria, progressive weakness, ataxia and seizures, increased serum CK and ragged-red fibers on muscle biopsy (CoQ10 reductase deficiency) 5) mitochondrial encephalopathy (excluding MELAS) (NADH-CoQ reductase or complex I deficiency), 6) various combinations of weakness, short stature, dementia, ataxia, sensorineural deafness, retinitis pigmentosa, sensory neuropathy and pyramidal signs (complex III deficiency).

Fatty acid oxidation defects (FAODs): FAODs usually present with a history of hypoglycemia or coma after sustained exercise or prolonged fasting (>24 hours), intermittent bouts of weakness, lethargy, ataxia and coma or episodic vomiting. In addition, disorders of lipid metabolism may cause two main clinical syndromes, namely (1) progressive weakness (long- and very long-chain acyl-CoA dehydrogenase (LCAD, VLCAD), and trifunctional enzyme deficiencies) or (2) normal muscle strength between attacks with episodes of acute, recurrent, reversible muscle dysfunction with exercise intolerance, cramps and acute painful rhabdomyolysis or myoglobinuria (with or without myalgia) induced by fever, fasting or prolonged exercise, valproate therapy, cold exposure (carnitine palmitoyltransferase II (CPT II) deficiency or (3) both (LCAD, VLCAD, short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD), and trifunctional enzyme deficiencies). CPT II is the commonest FAOD and the most common cause of recurrent myoglobinuria. The age of onset in the adult form is typically in the 2nd or 3rd decade of life. Rest does not abort the attacks and there is no second-wind phenomenon. Hypoglycemia with minimal-to-absent ketonemia and ketonuria, mild lactic acidosis, hyperammonemia, and reduced plasma carnitine levels. CK levels are normal or mildly elevated (50%) between attacks. During attacks serum CK levels may rise to 100,000 U/L. Iv glucose improves exercise tolerance while oral glucose is not effective. Assays are available for the measurement of CPT I and II in circulating lymphocytes and cultured fibroblasts. All of the other b-oxidation defects are characterized by dicarboxylic aciduria (urine analysis (fasting) for organic acids). Identification of the specific enzyme requires tissue (muscle, cultured fibroblasts) analysis. CPT is inherited as autosomal recessive trait but occurs most commonly in young adult males. The gene has been mapped to chromosome 1p12. McArdle disease needs to be differentiated from CPT II deficiency. Treatment consistes of frequebt meals, low fat high carbohydrate with avoidance of fasting.

L-2-hydroxyglutaricaciduria: This autosomal recessive disorder may present in the 1st –2nd decade of life and is characterized by cognitive delay, seizures, progressive ataxia, dysarthria and extrapyramidal dysfunction. Plasma, urine and CSF 2-hydroxyglutaric acid levels are increased.  Lysine is increased in plasma and CSF.

Wernicke encephalopathy: The triad of acute confusion, ataxia and ophthalmoplegia is typical for Wernicke syndrome. Beriberi polyneuropathy is often found and consists, in contrast to alcoholic polyneuropathy, of non-painful motor neuropathy affecting distal leg muscles. Painless nutritional optic neuropathy or "nutritional amblyopic or tobacco-alcohol amblyopia" may occur. Initially, blurring or fogging is noticed at the point of fixation, followed by a progressive decline in visual acuity, which may be rapid. Visual field defects are nearly always central or cecocentral. The diagnosis of Wernicke encephalopathy is very suggestive after glucose load in chronic malnourished alcoholics but also occurs in other thiamine deficiency states (parenteral malnutrition, hyperemesis, impaired gastrointestinal function). Thiamine status can be evaluated by measuring total thiamine concentration in whole blood (>20 ng/ml) and erythrocyte transketolase activity (>124 U/L). Abnormal T2 and FLAIR sequences on MRI in mamillary bodies, periaquaductal gray matter, hypothalamus, dorsal medial thalamus are found. Diffusion-weighted imaging can be diagnostic early after injury and indicate injury before onset of necrosis. Mammillary body atrophy is an irreversible marker of chronic Wernicke encephalopathy and is best assessed on sagittal or coronal MRI.  Aggressive vitamin B1 therapy (100 mg/day, initially iv) should improve the neurological status of the patient. Improvement in ocular symptoms of Wernicke encephalopathy is universal and rapid, often within hours. Most patients with Wernicke encephalopathy will show complete recovery of extraocular motility, although a horizontal nystagmus may persist. Ataxia responds somewhat later, and only 40% of patients recover completely. The global confusional state also recedes, but 80% of patients with Wernicke encephalopathy are left with a residual memory disorder or a Korsakoff amnesic state. Most Korsakoff patients had initially evidence of Wernicke encephalopathy. Thus, both entities are commonly regarded as two facets of the same disease process, resulting from thiamine deficiency. Korsakoff syndrome, refers to an abnormality of mentation in which memory and learning are affected out of proportion to other cognitive functions, in an otherwise alert and responsive patient. Always search for hidden history of alcohol dependence.

Systemic vasculitis: PACNS, SLE, Sjögren syndrome, PAN, Wegener granulomatosis, Churg-Strauss syndrome, and Behçet disease. Although MRI and cerebral angiography may both be negative, MRI is usually associated with white matter lesions and cerebral angiography may show segmental narrowing of small blood vessels. A biopsy is needed for the diagnosis of PACNS.

Cerebrotendinous xanthomatosis: This a rare autosomal recessive disorder caused by mutation of the sterol 27-hydroxylase (CYP27) gene and resulting in defective bile acid synthesis. The adult form is almost invariably characterized by juvenile cataract (97%), progressive neurological dysfunction (spastic paraplegia (often very prominent) (81%), low intelligence (poor attention, memory impairment) (66%) and cerebellar ataxia (56%)), chronic intractable diarrhea (since childhood) (50%) and bilateral Achilles tendon xanthomas (41%). Less frequently, seizures, sensorimotor demyelinating peripheral neuropathy and premature cardiovascular disease may occur. Serum cholesterol levels are reduced and cholestanol levels are increased (normal 0.2 + 0.2 mg/dl). Brain MRI scan reveals consistently bilateral signal hyperintensities in the dentate nuclei on FLAIR. Proton MR spectroscopy appears to be a useful measure of disease outcome. Treatment chenodeoxycholic acid can reverse neurological syndrome.

Abetalipoproteinemia or Bassen-Kornzweig syndrome: Almost 50% of patients with abetalipoproteinemia present with neurological manifestations. Age of onset is usually in the 1st or 2nd decades of life. Loss of night vision and steatorrhea are frequently the earliest symptom and precede weakness of the limbs with areflexia and sensory ataxia, later followed by cerebellar ataxia. Steatorrhea causing vitamin (A, E and K) malabsorption results in progressive unremitting spinocerebellar ataxia with loss of proprioception and vibratory sensory loss (tabetic type of sensory ataxia), areflexia and weakness (vitamin E responsive peripheral neuropathy), INO with nystagmus of adducting eye and retinitis pigmentosa (in later stages). Gastrointestinal symptoms may be mild or subclinical. ESR is low. Fresh blood smear with acanthocytes with hypolipidemia (reduced serum total cholesterol, apoprotein B (necessary for chylomicron formation), absent b-lipoprotein and low or absent chylomicrons, LDL-cholesterol and VLDL (essential for vitamin E transport)), low levels of plasma prothrombin, very low vitamin E and low serum levels of other fat soluble vitamins (except vitamin D which has its own transport system) are diagnostic. Urinary mevalonic acid levels are increased. NCVs reveal axonal neuropathy. SSEPs, VEP and ERG are abnormal. Sural nerve biopsy shows diminished numbers of myelinated fibers. The disease is autosomal recessive and caused by deficiency of microsomal triglyceride-transport protein (MTP gene mapped to chromosome 4q22-24). PET scan shows reduced [18F]dopa uptake in both putamen and caudate nucleus in severe and prolonged vitamin E deficiency. By the 2nd or 3rd decades patients are often bedridden. The syndrome needs to be differentiated from FA. Familial hypobetalipoproteinemia: Homozygous patients are clinically indistinguishable from patients with abetalipoproteinemia. They generally have low levels of apoprotein B, betalipoproteins, total cholesterol and LDL-cholesterol, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome). Heterozygous patients are usually asymptomatic are have part of the syndrome. The disorder is autosomal dominant and is caused by mutations in the apoprotein B gene (chromosome 2p24).

GM2 gangliosidosis (hexosaminidase deficiency): Late-onset forms of GM2 gangliosidosis: Tay-Sachs disease (hexosaminidase A deficiency) and Sandhoff (hexosaminidase A and B deficiency) disease exist. Late-onset forms (age of > 60 years) of GM2 gangliosidosis occur particularly in Ashkenazi Jew descendants, but have been identified in other populations as well. Early and dominant sensory disturbances (axonal sensory polyneuropathy) such as mechanoallodynia are often the first symptoms. In addition, almost half of the patients present with psychiatric manifestations (psychosis), slowly progressive SMA with muscle weakness (often limb-girdle in distribution) and nocturnal cramps and other combinations of MND (fasciculations, spasticity and amyotrophy), progressive spinocerebellar ataxia and ophthalmoplegia. Other manifestations such as dementia, dystonia, and seizures are less common. In contrast to chronic (or adult) GM1 gangliosidosis, extrapyramidal features (dystonia, parkinsonism) are not a prominent feature and are explained by the fact that in chronic (or adult) GM2 gangliosidosis storage neurons are more widely distributed (thalamus, substantia nigra and other brainstem nuclei, and cerebellum). MRI may reveal severe cerebellar atrophy. The diagnosis is based on serum and leukocyte total hexosaminidase (Sandhoff disease) and hexosaminidase A (Tay-Sachs disease), which decreased in both conditions (2 to 4% of normal). Further confirmation can be received from rectal biopsy (ganglion cells). GM2 gangliosidosis is autosomal recessive and the HEXA gene is located on chromosome 15q23-24. All patients with recessive atypical ataxia or unusual motor neuron disorder should be screened for lysosomal storage disease, particularly if the parents are consanguineous. The disease may mimick progressive muscular dystrophy.

Idiopathic late onset cerebellar ataxia (ILOCA): The age of onset tends to be later than in SCA, with a mean average of 50 years. The progression is relentless and patients lose the ability to walk independently between 5 and 20 years from onset. Clinically, ILOCA differs from SCA by the absence of optic atrophy and retinopathy. The condition most frequently confused with ILOCA is OPCA. The fast clinical progression with patients being wheelchair bound after 6 years and the presence of autonomic impairment may favor the diagnosis of MSA (OPCA).

Opsoclonus-myoclonus ataxia syndrome: Although mostly encountered in infancy, adult forms exist.  About 50% of them are idiopathic, others are viral (EBV, AIDS) or paraneoplastic (small-cell lung, gynecologic and breast cancer) and associated with anti-Ri antibodies in patients with breast cancer. A unique feature is the response to corticosteroids and ACTH. Mild CSF pleocytosis can be found and brain MRI is usually normal.

Refsum disease: Onset is usually in the 2nd or 3rd decade. The course of the disease may be subacute, progressive or relapsing. The tetrad of Refsum disease consists of delayed retinitis pigmentosa (may precede the biochemical abnormalities by years), cerebellar ataxia, distal demyelinating predominantly motor polyneuropathy and elevated CSF proteins without pleocytosis (albuminocytologic dissociation). In addition, progressive deafness, diabetes and heart failure resulting from cardiomyopathy are present in most cases. Other clinical features, less commonly found are cataract, ichtyosis, anosmia, diffuse skeletal hyperostosis, liver and kidney disease. Night blindness is the first symptom followed by progressive demyelinating symmetric distal neuropathy (affecting predominantly vibration and proprioception in the legs more than the arms) and ataxia. Peripheral nerves may be hypertrophic. In contrast with the degree of retinitis pigmentosa, the neuropathic findings and cardiac involvement correlates very well with the plasma phytanic acid levels. Plasma phytanic acid is increased (normally < 0.2 mg/dl), but normal phytanemia has been reported. In the latter the issue needs to be resolved by determination of the activity of phytanic acid oxydase in skin fibroblasts. Sensory and motor NCVs are very low < 10 m/s. Brain MRI may show cerebellar atrophy. The disorder is autosomal recessive and caused by mutation in the phytanoyl-CoA hydroxylase gene (chromosome 10pter-p11.2). Heterozygous carriers do exist and can be identified by the activity of phytanic acid oxydase in cultured fibroblasts. Cardiac failure may be the cause of sudden death.

Familial paroxysmal episodic ataxia (EA): Familial episodic ataxias are unusual autosomal dominant disorders of early onset (before the age of 20) characterized by recurrent episodes of cerebellar ataxia. Most patients recover fully between attacks, but some may develop progressive ataxia with cerebellar atrophy. Stress, exercise and fatigue can trigger ataxic spells, which can respond dramatically to acetazolamide. Different types of EA have been identified: EA type 1, with myokymia and epilepsy, and attacks which usually last seconds to minutes, and may occur several times a day. Vertigo is present during episodes, but no nystagmus. Continuous myokymia between attacks are charateristic. Kinesigenic provocation (movement, startle or emotion) is common. EA1 is mapped to chromosome 12p13 and linked to mutations in KCNA1 (voltage-gated potassium channel gene). EMG shows continuous motor unit acitivity in all patients.; EA2 with interictal nystagmus, is long-lasting (hours) associated with attacks of vertigo, diffuse weakness, slurred speech, dystonia, seizures, truncal and limb ataxia and downbeat nystagmus, often associated with nausea, vomiting and headache (migraine, often hemiplegic migraine). The disease is often mistaken for MG. Provoking factors are stress, exercise and fatigue. EA2 is mapped to chromosome 19p13 and linked to mutations in CACNA1A (a calcium channel gene). The latter mutations have also been identified in familial hemiplegic migraine and SCA-6. Acetazolamide may be effective; paroxysmal choreoathetosis with EA, with attacks lasting for about 20 min and occurring at varying intervals.

Kuru: The disease is prevalent in ritual cannibalistic New Guinea and presents clinically with progressive cerebellar ataxia, abnormalities of extraocular eye movements, weakness and incontinenece. Death occurs in 3 to 6 months of onset. Brain MRI reveals abnormalities in thalamus and limbic system.

Whipple disease: This rare disorder is predominantly found in middle-aged men. The triad of cognitive changes (half of them with psychiatric features) (71%), myoclonus (31%) and eye movement abnormalities (vertical supranuclear gaze palsy, INO, oculomasticatory or facial-skeletal myorhythmia) (20%) is diagnostic for Whipple disease but is only found in 10% of patients. In addition, focal cerebral and cerebellar syndrome, aseptic meningitis (mild pleocytosis with occasssionally PAS positive material), headache and epilepsy may be found. This may occur independently of the gastrointestinal malabsorption (steatorrhea, abdominal pain and distention, weight loss, wasting) or systemic features (hyperpigmentation, fever of unknown origin, lymphadenopathy, longstanding remitting and relapsing arthropathy) of the disorder (up to 15%). The diagnosis is established by small bowel biopsy or more reliable by PCR on biopsy or CSF. The causative agent is Tropheryma whippelii, which can be found in bowel and brain tissue. Neuroimaging is non-specific and may mimic TB, sarcoidosis, AIDS, MS and encephalitis. Most commonly the disease is misdiagnosed as AD and later on CJD. Other differential diagnosis include neurosarcoidosis and cerebral vasculitis.

Multiple system atrophy (MSA): MSA, also called "Parkinson Plus” syndrome, is estimated at 0.04 in the general population. The mean age of MSA onset is 52.5 years ranging from 30 to 70 years and consists of the following clinical subtypes: MSA-P (predominantly parkinsonism) and MSA-C (predominantly cerebellar ataxia) however the predominance can change over time. Varying degree of parkinsonism and autonomic dysfunction (urogenital dysfunction and orthostatic hypotension) are the common and prominent initial clinical manifestations of MSA. Later on followed by cerebellar ataxia (49%) and pyramidal involvement (61%). There is no clinical feature that clearly distinguishes MSA-P from IPD, but tremor is less prominent, response to levodopa therapy is poor, and cervical dystonia (anterocollis) is more prominent in the former. The extremities are dusky (violet in appearance indicating autonomic dysfunction), the voice is squeaky, there is early hand dystonia and ocular dysmetria (overshoot). Furthermore the clinical features of MSA in general are governed by rapid progressive asymmetrical limb rigidity with bradykinesia and jerky postural, intention tremor or no tremor at all. Other clinical signs include early falling and fine myoclonic jerks of the fingers/limb and can be elicited by tapping the limb. The cerebellar syndrome is usually subtle with gait and limb ataxia, nystagmus and dysarthria. Similarly, pyramidal signs are also subtle e.g. increased tendon reflexes, extensor plantar response, pseudobulbar syndrome, or mild spasticity. Autonomic dysfunction consists of orthostatic hypotension (68%), urgency and frequency of micturition (55%) or impotence (80%) prior to the start of levodopa therapy. Other signs may include respiratory irregularities (inspiratory stridor), severe antecollis (“sunflower” appearance or also called camptocormia) and sometimes mild eye movement and REM sleep abnormalities. Dementia occurs rarely. Ancillary investigations for MSA should include autonomic function tests, brain MRI and external urethral and anal sphincter EMG (false positive for PSP).  Reduced striatal 131I-iodobenzamide binding is suggestive for MSA and has successfully predicted levodopa responsiveness. In MSA, there is little (30-50% of patients respond) or short-lived response (1-2 years) to levodopa and atypical orofacial levodopa-induced dyskinesias rapidly develop. MSA should be differentiated from ILOCA and hereditary late-onset SCA, by the presence of autonomic impairment and lack of family history. Progressive autonomic failure (PAF) differs from MSA by the slower onset and progression, absence of associated neurological features, no REM sleep abnormalities, no syncope or postprandial hypotension. Furthermore in PAF, autonomic function tests indicate peripheral autonomic dysfunction. In contrast to PSP, no ophthalmoplegia is observed. On T2 weighted MRI of the brain, in MSA-P the putamen shows reduced signal running up the lateral extent (increased iron deposition) and this may be covered by a rim of increased signal. If there is associated MSA-C the lateral as well as longitudinal pontine fibers become evident as high signal (“hot cross bun” sign = cross-shaped T2 signal hyperintensity within the pons) and pontine or cerebellar atrophy may also be present. The disease progression of MSA is abnormally rapid and median survival is about 10 years.

Subacute necrotizing encephalopathy (SNE) or Leigh disease: Several synonyms exist such as Leigh necrotizing encephalopathy, Leigh syndrome and necrotizing encephalomyelopathy of Leigh. Adult-onset forms of SNE are sporadic, or inherited in an autosomal recessive, autosomal dominant, X-linked, or mitochondrial trait. To complicate matters even more several different types of genetically determined enzyme defects can cause SNE. As with other mitochondrial disorders, the onset of neurologic symptoms present from the 1st - 6th decade with acute or subacute onset, often precipitated by surgical intervention or febrile illness. The disease can present with a variety of symptoms such as brainstem dysfunction (central respiratory failure, intermittent oculomotor palsy, cranial nerve dysfunction including deafness, optic atrophy or Wernicke-like syndrome), ataxia, or extrapyramidal (dystonia) symptoms, global cognitive dysfunction (dementia or mental retardation (30%)), spastic paresis, myoclonic jerks and seizures, peripheral demyelinating polyneuropathy, motor decline and unconsciousness with lactic acidosis. In addition, insulin-resistant diabetes mellitus, muscular weakness, intractable nausea and vomiting, and anemia can occur. The disease can be intermittent progressive or remitting/relapsing. CSF protein may be increased. Brain MRI shows abnormal high intensities in basal ganglia, particularly putamen, on T2 weighted images, bilateral medial regions of the thalamus, brainstem and periaqueductal gray matters. Proton MRS may show elevated lactate level in involved regions of the brain. Ragged red fibers can be found on muscle biopsy with increased succinic dehydrogenase activity and cytochrome oxidase negative fibres in almost 90% of cases. Pre- and postprandial serum and CSF lactate and pyruvate are useful in the diagnosis. Serum lactate is increased in 50% of patients but is less sensitive than CSF lactate. Pyruvate dehydrogenase deficiency (or Lactic and Pyruvate Acidemia with Episodic Ataxia and Weakness) presents with episodic ataxia, seizures, and hypoglycemic episodes and may mimic SNE. Serum and urine amino acid analyses reveal hyperalaninemia. Treatment for SNE is empirical but the administration of thiamine, coenzyme Q10 have been used. The prognosis is usually bad with survival rates less than a few years after onset.

Panthotenate kinase-associated neurodegeneration or Hallervorden-Spatz disease (HSD): The adult onset form of this autosomal recessive disorder presents in early adulthood with atypical parkinsonism (initially affecting the legs or bulbar musculature), ataxia, myoclonus, dystonia (tongue or blepharospams), chorea or dementia. Most patients also develop pyramidal syndrome and seizures (20%). T2 weighted brain MRI shows an ”eye of the tiger” sign corresponding to pallidal hypointensity with a high signal center. Very low signal intensity is also seen in the red nucleus, and substantia nigra, consistent with increased iron deposition in these structures. Bone marrow contains sea blue histiocytes. The gene locus (PANK2) has been identified on chromosome 20. Treatment of patients with HSD is largely symptomatic. Many patients, especially in the early stages of the disease, may respond modestly to levodopa treatment. Variants have been reported such as HARP syndrome (hypoprebetalipoproteinemia [very low VLDL], acanthocytosis, retinitis pigmentosa, and pallidal degeneration). The dystonia affects cranial musculature and MRI findings are those of HSD. HSD needs to be differentiated from WD, juvenile HD, SNE, PD, DRD, Fahr disease, Lafora body disease (EPM2), MS, DRPLA, Kufs disease, gangliosidoses and APBD.

Dentatorubropallidoluysian atrophy (DRPLA): Although described chiefly in Japan, European families are also affected by this autosomal dominant condition. It is caused by a CAG repeat expansion mutation of atrophin 1 gene mapped to chromosome 12p13 (Boston University Center, Human Genetics Laboratories).  The age of onset of symptoms ranges from adolescence to the 6th decade of life and the presentation is quite heterogeneous. Three phenotypes have been described the ataxo-choreoathetoid type, a pseudo-Huntington type, and a myoclonic epileptic type. Hence clinical features include progressive cerebellar ataxia, or dementia with chorea, or prominent chorea and dystonia or progressive myoclonic epilepsy. Variants (Haw-River syndrome) of the disease exist (subcortical demyelination; neuroaxonal dystrophy; no seizures). Brain MRI scan shows cerebellar and brainstem atrophy and multiple WMHIs on T2 sequences. DNA analysis is essential for the diagnosis. Homozygotes for DRPLA genes may have recessive predominantly spinal syndrome which has its onset in the 3rd or 4th decade and consists of spastic paraplegia, loss of vibratory in the lower limbs and truncal ataxia. In view of its resemblance DRPLA is often confused with HD.

Niemann-Pick disease type C (NPC): This autosomal recessive disorder is almost invariably characterized by two major features: psychomotor retardation and supranuclear downgaze paresis. In addition, ataxia, extrapyramidal features (dystonia) and seizures occur. In late-onset cases progressive dementia or psychosis may be the major presenting manifestation besides supranuclear downgaze paresis, extrapyramidal features and seizures. Unlike in early-onset cases visceromegaly is usually mild. The diagnosis is based on the triad of vertical gaze paresis, organomegaly and foam cells (sea blue histiocytes) in the bone marrow. A confirmatory test is the determination of the rate of cholesterol esterification in cultured skin fibroblasts. The NPCI gene is located on chromosome 18q11-12. Brain MRI is usually normal or may show demyelination. Death usually occurs from aspiration and intercurrent pulmonary infection.

Kufs disease type A (adult neuronal ceroid lipofuscinosis): In adolescence to middle age adulthood, two clinical Kufs phenotypes emerge; type A, featuring progressive myoclonic epilepsy with marked photosensitive and generalized tonic-clonic seizures developing at around the age of 30 years with subsequent ataxia, and dysarthria, dementia, and later pyramidal and extrapyramidal signs. There are no visual problems and seizures are often refractory; and type B, dominated by neuropsychiatric symptoms, including behavioral disturbances and dementia, and may be associated with cerebellar or extrapyramidal signs (cranial dystonia including facial dyskinesias or parkinsonism). The dementia syndrome is characterized by gradual onset, progressive course, and deficits in episodic memory, executive function, and visuospatial abilities; these features and the pattern of cognitive dysfunction thus overlap those of more common neurodegenerative dementing illnesses, including AD. Dementia may be the presenting symptom of Kufs disease and may not be manifested until the seventh decade of life. Unlike other forms of neuronal ceroid-lipofuscinosis, it does not cause blindness. Electrophysiologic and neuroradiologic studies are nonspecific. Giant VEP and large SSEPs can be elicited. Abnormal photic drive (high-amplitude spike at low rates of stimulation) is observed during EEG. Brain MRI may show predominantly cerebellar atrophy and signal changes on T2 in the putamina. The diagnosis is based on the presence of granular osmiophilic deposits found by EM in rectal, muscle, skin or liver biopsy and are deficient in lysosomal palmitoyl protein thioesterase. Urinary sediment dolichol levels are elevated in both types. The disease is autosomal recessive (rarely dominant) and caused by mutation in CLN3 gene of which the locus is unknown. Kufs disease should be considered when seizures and motor disturbances complicate the early course of atypical dementia in middle adult life. Visual loss and optic atrophy are unusual and in combination with the later age at onset clinically distinguished Kufs disease from other NCLs. Mean length of illness is about 7 years.

Krabbe leukodystrophy (KLD): Three adult forms of this slowly progressive autosomal recessive disorder have been reported: (1) familial spastic paraplegia or tetraplegia, (2) an asymmetric pyramidal syndrome and (3) an asymptomatic form. Later on features such as frontal dementia, seizures, cerebellar ataxia, optic atrophy and demyelinating sensorimotor peripheral polyneuropathy appear. Motor nerve conduction is substantially reduced (NCVs may however be normal). CSF protein levels may be normal. Brain MRI may be normal but most often reveals increased signal intensity on T2 in the spinal pyramidal tracts, bilateral in the white matter of the cerebrum and brainstem. Proton MR spectroscopy shows increased choline and myoinositol in affected white matter. The diagnosis is based on the presence of low lysosomal galactocerebrosidase activity (<5% of normal) in white blood cells or cultured dermal fibroblasts. Some healthy individuals may have low enzyme activity. The gene maps to 14q25-31.

Metachromatic leucodystrophy (MLD): The late-onset form of this slow progressive autosomal recessive disorder has classically been described as presenting in its adult form with psychiatric manifestations; behavioral problems and slowly progressive dementia (frontal or subcortical in nature). But in fact two distinct geno-phenotypes are found: those patients presenting initially with motor disturbance (spasticity) and cerebellar dysfunction (arylsulphatase A mutation P426L homozygotes) and followed at later age by psychiatric manifestations, and those with schizophrenic-like behavioral abnormalities, social dysfunction, and mental decline, but scarce motor deficit (arylsulphatase A mutation I179S heterozygotes). At later age both clinical pictures merge or overlap. NCVs reveal substantially impaired motor nerve conduction (segmental demyelination) even in the absence of clinical features of polyneuropathy. CSF reveals raised protein levels. Some patients may develop abdominal symptoms related to sulphatide gallbladder stones. Brain MRI shows periventricular leukodystrophy (with frontal predilection) or can be normal. A convenient way to demonstrate MLD is the sulphatide excess in urinary sediment. The laboratory diagnostic tests show marked decrease or absence of arylsulphatase A activity in the urine and white blood cells or cultured skin fibroblasts. Sural biopsy reveals accumulation of metachromatic material. Important to know is that 1/50 to 1/100 of the normal population are homozygous for a common pseudodeficiency mutation in the arylsulphatase A gene (P426L, chromosome 22q). The work up for MLD deserves attention in any atypical MS-like syndrome or peripheral neuropathy of unknown origin. The course is prolonged and survival into 5th and 6th decade is possible.

Sialidosis type I or cherry-red spot – myoclonus syndrome: Type I sialidosis is the mild form and starts in adolescence or adulthood (2nd or 3rd decade of life) presenting with bilateral macular cherry-red spots and bilateral perinuclear cataracts (progressive loss of visual acuity), progressive cerebellar ataxia, progressive myoclonus (affecting the limbs and triggered by voluntary movements) and seizures (tonic-clonic) and mild peripheral polyneuropathy (burning feet). No dismorphic features are present. The diagnosis is made by elevated urinary sialyloligosaccharides, vacuolated white cells and foam cells with white cell a-N-neuraminidase deficiency. The mutated sialidase gene is located on chromosome 6p21.3. MRI may reveal severe atrophy of the cerebellum, pontine region, cerebral hemispheres and corpus callosum. Sialidosis is inherited as an autosomal recessive genetic trait.

Unverricht-Lundborg disease (EPM1): This autosomal recessive disorder with severe stimulus-sensitive myoclonus and generalized tonic-clonic seizures typically begins between the age of 6 to 15. Seizures become less frequent in young adult life. Progressive cerebellar ataxia develops in addition to mild dementia. The disease is prevalent around the Baltic area. Unlike in other PMEs, no inclusion bodies or storage material are found. With exclusion of other forms of PME, generalized epileptiform discharges on EEG activated with intermittent photic stimulation are pathognomonic. The gene (cystatin B) responsible for the disorder is mapped to chromosome 21q22.3. Brain MRI reveals loss of bulk of basis pontis, medulla, cerebellar hemispheres, and widening of the interhemispheric cerebral sulci due to atrophy. Life expectancy is over 60 years of age, but disability is often severe. Piracetam has been useful in the treatment of myoclonus. Phenytoin aggravates symptoms.

Lipodystrophy: Neurological disorders have been associated with generalized lipodystrophy (mental retardation, third ventricle dilatation and hypothalamic hamartomas) and with partial lipodystrophy (myelopathy, ataxia, epilepsy, deafness, cataract, retinitis pigmentosa, mental retardation and basal ganglia calcification). The partial form usual starts early in adulthood and progresses to profound debility. Associated metabolic abnormalities are hypertriglyceridemia, and insulin resistance with impaired glucose tolerance. Differential diagnosis include mitochondrial disease, peroxisomal disorders and disorders of glycosylation. The disorder is autosomal dominant and has been associated with mutations on chromosome 9q34, 11q or 1q21-23.

Lafora-body disease (EPM2): This is an autosomal recessive disorder with late childhood or teenage onset and is characterized by progressive myoclonus and generalized tonic-clonic epilepsy (photoconvulsive seizures), drop attacks, ataxia and rapidly progressive dementia. Brain MRI shows often cerebellar atrophy. The diagnosis is made by biopsy (skin, muscle, liver, brain) showing periodic acid-Schiff positive glycogen-like intracellular inclusion bodies (Lafora bodies). The mutation in the EPM2A gene which codes for laforin and which probably prevents accumulation of polyglucosans bodies in healthy neurons has been mapped to chromosome 6q24. The second type is a mutation in EPM2B gene which codes for E3 ubiquitin ligase (malin). Prognosis is poor (death within 10 years). Other forms of autosomal recessive PME are Unverricht-Lundborg syndrome (EPM1), Mediterranean and Baltic myoclonus epilepsy syndrome. The latter is accelerated by phenytoin.

Celiac disease (or gluten sensitive enteropathy): Celiac disease affects 0.5-1% of the Caucasian population. The age of onset may vary between 40 - 80 years and the mean duration of ataxia between 3 - 25 years. Half of the patients do not present with gastrointestinal symptoms (gluten-sensitive enteropathy or celiac disease). Conversely, 10% of celiac patients have an associated neurologic disease, most often peripheral neuropathy or ataxia. Gluten sensitivity is found in 27% of sporadic and 37% of autosomal dominant ataxia patients. Neurologic manifestations and dermatitis herpetiformis can occur without histological evidence of bowel involvement. Majority of patients presenting with neurologic symptoms have peripheral neuropathy (often painful sensory neuropathy presenting as distal paresthesias) or cerebellar ataxia ("gluten ataxia"). Other neurological features may include episodic unilateral headache with visual disturbances (hemianopia), deafness, encephalopathy (confusion, agitation, dementia), myelopathy, cerebral calcification and seizures. Some patients develop Ramsay-Hunt syndrome. The diagnosis is based on the presence of serum IgA anti-gliadin (found in up to 12% of the normal population), IgA endomysial and transglutaminase antibodies and confirmed by small bowel biopsy. Up to 90% of patients with celiac disease are HLA DQ2, the remaining have DQ8 or DQ1. NCVs can be normal or minimally abnormal axonal neuropathy. Sural biopsy reveals axonopathy. Brain MRI abnormalities vary from confluent areas of high signal throughout the white matter to foci of high signal scattered in both hemispheres. Only 33% of patients presenting with neurologic dysfunction associated with gluten sensitivity also have celiac disease. Gluten ataxia accounts for 40% of cases of idiopathic sporadic and familial cerebellar degeneration. The neurological manifestations may not respond to a gluten free diet. Common non-neurological presentations except for chronic diarrhea are iron deficient anemia and osteoporosis. Associated inflammatory conditions are type I diabetes, Sjögren syndrome and thyroiditis. The risk for first degree relatives to develop celiac disease is 13%.

Leber hereditary optic neuropathy (LHON): These comprise a group of disorders presenting with cecocentral scotoma, negative imaging and a positive family history. LHON is a mitochondrial disorder usually affecting men between the age of 15-35 years and presents with acute or subacute painless visual loss in one eye, the next eye following weeks or months later. Progressive cerebellar ataxia, hyperreflexia, peripheral neuropathy and cardiac conduction abnormalities are also common findings. Fluorescein angiography may help distinguishing the LHON optic disc from true disc edema. ERG, and CSF are normal. Dystonia may occur which may be accompanied by the presence of striatal lesions on MRI. The work up will require a blood sample for mitochondrial DNA analysis may include primary mutations at T3394C, G3460A, A4136G, T4160C, T14484C or G11778A, the latter having the worst prognosis. Asymptomatic maternal relatives have abnormal fundi. Early onset ataxia with optic atrophy are a heterogenous group of disorders which can occur in combination with Friedreich ataxia, X-linked ataxia, leucodystrophies ALD, KLD, sialidosis, MELAS, biotin deficiency or demyelinating disease. CPEO, MNGIE, NARP and KSS are two other mitochondrial disorders associated with optic neuritis.

Wilson disease (WD): The prevalence of the disease is around 1/100,000 in the general population. Early onset (2nd to 3rd decade of life) or atypical parkinsonism (particularly affecting the bulbar musculature) in the presence of liver dysfunction or psychiatric abnormality should suspect WD. Alternative clinical presentations may be the dystonic or cerebellar form. Dysarthria, sialorrhea and personality change, gait abnormalities and arm tremor account for the majority of presenting symptoms and signs. The diagnosis is based on the triad of Kayser-Fleischer ring (slit lamp examination), low serum ceruloplasmin (levels are low in 90% to 95% of individuals with WD, but can also be low in asymptomatic carriers or can be normal in 5-10% of patients with the disease) and elevated 24-h urinary copper excretion (best confirmatory test; if greater than 100 mg/24 hours, levels < 50 mg/24 hours rules out WD). Since false positive or negative tests occur liver biopsy will settle the matter (copper levels exceeding 250 mg/g dry weight are diagnostic). Kayser-Fleischer ring is present in all patients with neurologic or psychiatric disease and its presence may antedate overt symptoms of the disease. There is no correlation between the degree of brain pathology and the clinical presentation. Brain MRI is usually abnormal in those with neurologic or psychiatric disease, but may be completely normal in those with pure liver disease. MRI may show increased signal in the midbrain (“face of the giant panda”), basal ganglia, ventrolateral thalami, posterior limb of the internal capsule, or middle and superior cerebellar peduncles on T2 and proton-dense images but are not specific. The disorder is autosomal recessive and the gene mutation has been mapped to chromosome 13q14.3, which encodes for a copper transporting P-type ATPase (ATP7B protein). However there are a large number of mutations which can make the diagnosis impractical, unless a gene abnormality has been established in a given family. Slit lamp examination, serum ceruloplasmin and liver function tests are useful in screening of siblings at risk. Penicillamine is clearly efficacious, but it has many potential side effects: it can cause hypersensitivity reactions, induces the production of autoantibodies, which can ultimately lead to Goodpasture disease, MG, or SLE. Pyridoxine should be added to prevent anemia. The most worrisome side effect is the precipitant worsening in a patient's neurologic status after initiating penicillamine therapy. Up to 50% of patients with neurologic WD have sudden neurologic worsening. Of those, 50% experience permanent disability that is more severe than their clinical status when penicillamine was initiated. Any disability that persists 2 years after starting therapy will probably be permanent. However, the brain MRI may continue to show improvement for up to 4 years after therapy is initiated. Differential diagnosis which should always be considered are HD, HSD, neuroacanthocytosis, mitochondrial cytopathy, and a rare familial disorder called aceruloplasminemia.

Basilar migraine: The age of onset peaks in adolescence and the frequency decreases between the 3rd and 4th decades. This type of migraine fulfills the criteria for migraine with aura but has in addition at least two of the following aura symptoms: visual symptoms in both temporal and nasal fields of both eyes, dysarthria, vertigo, tinnitus, decreased hearing, diplopia, ataxia, drop attacks, bilateral paresthesias or paresis, impaired consciousness or amnesia. The aura lasts 5 to 60 minutes but may last up to 3 days. The severe throbbing headache is usually located bilateral occipital and nausea and vomiting as almost invariable present. The differential diagnosis includes partial seizures.

Intermittent metabolic ataxias: Carbamoyl phosphate synthetase type I deficiency (CPS I): In adults, some individuals remain unaffected until onset in early to mid adulthood. Symptom and signs of hyperammonemia including seizures, ataxia and tremor are the presenting manifestation. The sole laboratory criterion for early diagnosis is a blood ammonia level. Blood amino acids and urine organic acid analysis is important to rule out organic acid disorders. Carbamoyl phosphate synthetase deficiency is an autosomal recessive trait. The gene for this intramitochondrial hepatic enzyme is assigned to chromosome 2q35. Reduction of protein intake and attempt to maintain energy intake are the first steps in the treatment. Initiate iv infusion of 10% glucose (or higher, if administered through a central line) and lipids. Iv sodium benzoate and sodium phenylacetate may helpful. Ornithine transcarbamylase deficiency (OTCD): X-linked inherited OTCD is the most frequent urea cycle disorder (1 per 14,000). Many of the males die during the neonatal period. Late-onset OTCD occurs most commonly in female carriers who then develop symptomatic hyperammonemia. History of often postprandial headaches, recurrent episodes of ataxia, vomiting associated with psychiatric symptoms, seizures and unexplained somnolence or coma with brain edema. The alterations in mental state may last up to days. Very significant is the history of precipitation after infection and high protein meals (dietary protein intolerance since childhood). Hyperammonemia (1 hr postprandial) with normal pH (organic acidemia are acidotic), and plasma and urine amino acid screening (increased orotic acid in the urine) may suggest the diagnosis. Glutamine and alanine are elevated in blood and CSF. Liver biopsy and DNA analysis will be required for definitive diagnosis. Sodium valproate should be avoided in these patients. The chromosome has been mapped to Xp21.1. Other less common (autosomal recessive) urea cycle defects include argininosuccinic acidemia, carbamoyl phosphate synthase, citrullinemia and argininemia. These deficiencies manifest clinically in the same way and can be diagnosed by blood and CSF increase in the respective amino acids. Citrullinemia: Adult-onset type II citrullinemia is an inherited disorder of amino acid metabolism caused by a deficiency of liver specific argininosuccinate synthetase activity and is extensively reported in Japan. The age of onset of the encephalopathy ranges from 17 - 51 years. The clinical presentation is that of a history of repeated episodes of disturbance of consciousness (lasting from hours to days) e.g. sleep reversal, night terrors, and episodes of confusion or coma after meals (usually 2 hours followed by spontaneous recovery a few days later), or that of a chronic progressive psychotic illness. Chronic pancreatitis may precede the onset of encephalopathy. The diagnosis is based on the measurement of plasma and urine amino acids screening (hyperammonemia and citrullinemia) and plasma ammonia (1 h postprandial) with normal pH. Orotic acid in urine is abnormally elevated in citrullinemia. The diagnosis can be confirmed by assay of the enzyme in cultured fibroblasts. Brain MRI may be normal or show on T2-weighted images lesions bilateral in the cingulate gyri, globus pallidus, temporal lobes and insular regions, mimicking the finding of HSE. Brain MRI lesions may resolve after treatment. The disorder is autosomal recessive and maps to chromosome 9q34. Arginase deficiency: This autosomal recessive disorder presents with episodes of hyperammonemia associated with history of recurrent vomiting, episodes of ataxia, headache and dysarthria. A common clinical feature in this disorder is spasticity, and it is likely that the disease is underdiagnosed because many patients are categorized as cerebral palsy patients without effort to diagnose this disease. Blood and CSF arginine levels are increased. BUN is often very low (<3) in urea cycle disorders. Urinary amino acid excretion pattern with increased arginine, ornithine, lysine, and, possibly, cystine, can be observed due to competitive inhibition of dibasic amino acid reabsorption by elevated arginine. The chromosome has been mapped to 6q23. Argininosuccinic aciduria or argininosuccinate lyase deficiency: This autosomal recessive disorder presents with episodes of disorientation, ataxia and coma. The diagnosis is based on the determination of the plasma ammonia (1 h postprandial), plasma and urine amino acids (argininosuccinic aciduria). BUN is often very low (<3) in urea cycle disorders. The chromosome has been mapped to 7q21.3. Hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome (HHHS): The hallmark of this autosomal recessive disease consists of pyramidal tract dysfunction with aversion for protein-rich food and characteristic signs of hyperammonemia. Clinical features include spastic paraparesis, myoclonic seizures, mental retardation, and ataxia. Furthermore, there are recurrent acute episodes of hyperammonemia with loss of consciousness, lethargy and coma. Liver disease and coaguloapthy may occur. Age at onset may be variable (neonatal to early adulthood). The diagnosis is based on determination of plasma and urine amino acids, blood ammonia, and urinary orotate. Brain MRI may be normal or show basal ganglia calcifications or cortical atrophy. Liver and skin fibroblasts biopsy show giant megoconial mitochondria. The mutation has been identified in the gene that encodes for the mitochondrial ornithine transporter (SLC25A15 gene). Pyruvate dehydrogenase deficiency: This autosomal recessive syndrome of lactic and pyruvate acidemia with episodic ataxia and weakness presents with episodic ataxia, seizures, and hypoglycemic episodes and may mimic SNE. Serum and urine amino acid analyses reveal hyperalaninemia.

Gaucher disease: Three clinically distinct neurologic syndromes have been identified of this autosomal recessive lysosomal disorder characterized by β–glucocerebrosidase deficiency: type I (chronic non-neuronopathic), type II (acute neuronopathic), and type III (subacute or chronic neuronopathic). Adult forms have been reported in type I and III. Although non-neuronopathic, Gaucher type I may present with atypical PD in the 4th - 6th decade. The clinical course is usually severe with aggressive progression and is refractory to levodopa therapy. Gaucher type III (chronic neuronopathic form) is a chronic, slowly progressive neurologic disorder which may develop in early adult life. Stimulus-sensitive myoclonus, generalized seizures, horizontal supranuclear gaze palsies, and cerebellar ataxia are the main clinical features. Certain ethnic groups are at risk for this disorders; Gaucher type I is commonly found in Ashkenazi Jews (incidence of 1 in 2,500 births), while type III is more common in Northern Sweden (Norbotten). The diagnosis is based on the measurement of β-glucosidase activity in white blood cells. The clinical course is not predictable by measurement of residual β-glucosidase activity. The disorder is caused by a mutation in the gene on chromosome 1q21.

Ramsay-Hunt syndrome type II or dyssynergia cerebellaris myoclonica: This rare, degenerative, neurological disorder characterized by a triad of action myoclonus, epilepsy, severe cerebellar ataxia with cognitive impairment, starts generally in early adulthood. Tremor may begin in one extremity and later spread to involve the entire voluntary muscular system. Arms are usually more affected than legs. Treatment is symptomatic e.g. myoclonus and seizures may be treated with the drug valproate. The progression of the disorder is usually 10 years or longer. Many of these myoclonic ataxias can probably be classified as MERRF or Unverricht-Lundborg syndrome.

Myoclonic epilepsy with ragged red fibers (MERRF): The age of onset of this disease ranges from 5 – 75 years. The core clinical features of MERRF are myoclonus (often action, noise or photic stimulation-induced), progressive ataxia and seizures (drop attacks, focal seizures and photosensitive tonic-clonic seizures). Generalized myoclonic seizures are an early and consistent symptom only in a minority of patients with MERRF. Myopathy is usually proximal and mild (or may even be absent). Ragged-red fibers (not found in all patients) COX negative are the diagnostic histopathologic features in the muscle biopsy specimen. Additional features are progressive external ophthalmoplegia, progressive sensorineural hearing loss, peripheral neuropathy, foot deformity, basal ganglia calcification, short stature, deafness, OA and cervical lipomas. Insidious dementia may develop later in the course of the disease. Pigmentary retinopathy is found only in mtDNA mutations other than A8344G mutation. Plasma and CSF lactate levels can be elevated, but this is not a universal finding. The disorder is caused most commonly by a point mutation (A8344G) in the tRNA gene of mitochondrial DNA. The disorder can occur any time in adult life and the course is slowly or rapidly progressive. Maternal inheritance is an important feature that distinguishes MERRF from four other neurological syndromes dominated by progressive myoclonic epilepsy: Unverricht-Lundborg disease (EPM1), Lafora-body disease (EPM2), sialidosis type I and II, and Kufs disease.