(intermittent episodes of coma/behavioral abnormalities)
Metabolic disturbances: Hypoglycemic encephalopathy requires a 5-hour oral glucose tolerance test as well as peptide studies (insulin and C-peptide levels) and CT scan of the abdomen to screen for insulinoma. A search for multiple endocrine neoplastic syndrome should be carried out. Serum glucose levels in the 50 mg/dL range results in neuroglycopenic signs and symptoms of brain dysfunction (blurred vision, slurred speech, glassy-eyed appearance, confusion, and difficulty concentrating). Decreases of plasma glucose below 40 mg/dL frequently cause lethargy and gross behavioral abnormalities. In individuals with underlying cardiovascular disease, life-threatening arrhythmias, myocardial infarction and stroke may be precipitated by severe hypoglycemia, hyperammonemia and hyperinsulinemia.
Hypoperfusion from cardiac arrhythmias
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.
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).
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.
Carbamoyl phosphate synthetase type I deficiency: 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.
Methylmalonic acidemia: Defects in the common pathway of cobalamin reduction, leads to combined methylmalonic acidemia and homocystinuria, secondary to impaired adenosylcobalamin and methylcobalamin formation. Adolescents with the cobalamin C form of methylmalonic acidemia may present with progressive myopathy, lower leg hyposensitivity, and thrombosis due to the persistent homocystinuria in the cblC form of methylmalonic acidemia. The myopathy may not be reversible despite treatment, leading to continued gait disturbances. Urine organic acids reveal large amounts of methylmalonic acid and plasma amino acids typically show elevation of glycine. Brain CT/MRI scans typically demonstrate involvement of basal ganglia and white matter.
Propionic acidemia: This autosomal recessive disorder presents in adulthood with chorea, dementia, seizures and episodes of recurrent vomiting. Plasma, urine and CSF propionic acid levels (organic acids screening) are elevated and excretion of metabolites, including methylcitrate are typical. Propionic acidemia is due to propionyl CoA carboxylase deficiency (chromosome 3q13.3-22).
New variant Creutzfeldt-Jacob disease (nvCJD): Unlike for CJD, the mean age of onset of nvCJD is much younger (26-28 years) and the duration of the illness is longer (median duration 13 months, ranging from 6 to 39 months). Early signs of nvCJD can be either psychiatric and/or sensory symptoms. Psychiatric symptoms are dysphoria, withdrawal, anxiety, depression, apathy, weight loss, hallucinations, suicidal ideation and mild insomnia. Sensory symptoms consist of foot pain, dysesthesia/paresthesia of hands and face, legs, persistent cold feet, hemidysesthesia, hyperesthesia and pain in the lower limbs. Subsequently (usually within 4 months), patients develop overt neurological dysfunction with prominent sensory symptoms (if not yet present) memory impairment, ataxia dysarthria and rapidly progressive dementia, involuntary movements, incontinence and akinetic mutism. EEG is generally non-specific and not characteristic as in CJD. CSF analysis may show slight increase in protein. Testing for CSF 14-3-3 proteins is not useful in nvCJD. MRI shows bilateral increased pulvinar signal on T2-weighted images. Prion protein (PRNP) gene analysis shows methionine-methionine genotype at codon 129. Abnormal PRNP may be found in the tonsils of individuals affected with nvCJD.
X-linked adrenomyeloneuropathy (X-AMN): The adult form of this X-linked recessive peroxisomal disorder starts on average at the age of 28 years and is predominantly confined to the spinal cord (adrenomyeloneuropathy). Cerebral involvement is observed in half of the cases. X-AMN is often misdiagnosed as “familial MS”. Slowly progressive spastic paraparesis with sensory deficit (predominantly reduced vibratory sensation), bladder dysfunction and mild distal mixed axonal demyelinating polyneuropathy are common features. These clinical symptoms are often preceded or followed by behavioral disturbances or frontal dementia (mania, psychosis and cognitive impairment) and are often misdiagnosed as brain tumor. Both neuroleptic and anticholinergic medications may result in significant side effects with little resolution of the underlying psychiatric symptoms. Adrenal insufficiency (Addison syndrome) develops in 70% of the patients before, during or after the onset of the neurological syndrome, and does not correlate with the severity of the neurological disease. 20% of heterozygous female patients may develop a late middle age syndrome, which resembles adrenomyeloneuropathy (spastic paraparesis, loss of vibration, long tract signs and peripheral neuropathy), but are unlikely to develop adrenal dysfunction. Other phenotypes are pure adrenal insufficiency or simply asymptomatic carriers. The diagnosis is confirmed by the presence of increased levels of saturated VLCFA in plasma (15% false negative in female heterozygotes) and cultured skin fibroblasts or white blood cells. CSF reveals increased intrathecal IgG. NCVs in patients with X-AMN are often abnormal and suggest a mixture of axonal loss and multifocal demyelination. Although MRI can be normal in up to 50% of patients, high signal intensities in the periventricular parieto-occiptal white matter (often asymmetric and mimicking brain tumor) have been reported in cerebral forms. However in 15% the initial lesions may be frontal. MRI findings may often provide the first clue to the diagnosis. A decreased N-acetylaspartate/choline ratio is found on MR spectroscopy. BAEP reveals prolonged latencies of III-V. The defective ALDP gene encodes for ATP-binding cassette transporter involved in transport of VLCFA into peroxisomes and has been mapped to Xq28.
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. Occassionally, 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.
Subacute necrotizing encephalopathy (SNE) or Leigh disease: Several synonyms exist such as Leigh necrotizing encephalopathy, subacute 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 to 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 (dementia or mental retardation 30% of patients), 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, vitamin B1, Coenzyme Q10 have been used. The prognosis is usually bad with survival rates less than a few years after onset.