Hartnup's disease is an autosomal recessive transport disorder of neutral amino acids, affecting the kidney and small intestine and leading to excessive neutral aminoaciduria 5 to 20 times normal.1?! These monoamino/monocarboxylic amino acids include alanine, glutamine, histidine, serine, phenylalanine, tyrosine, tryptophan, asparagine, leucine, isoleucine, and valine but not proline. Plasma levels are normal. These same amino acids, particularly tryptophan, are retained in the gut and broken down by bacteria; and their breakdown products, indolic compounds, are excreted in the urine. Because tryptophan is excessively excreted in urine and not reabsorbed in the gut, it is not available for synthesis of niacin. Many subjects are discovered to have the aminoaciduria but have no clinical manifestations (Hartnup's disorder). When the disorder is symptomatic, it is called Hartnup's disease; and the main clinical manifestations are probably due to niacin deficiency, although the excessive indolic compounds may contribute to a metabolic encephalopathy. The actual carrier in the transport system or the gene responsible has not been identified. The biochemical phenotype is common, occurring in 1 in 30,000 newborns screened. However, only 10 percent or less actually develop the classical clinical phenotype. To develop the disease, multiple factors are probably involved--environmental, such as poor nutrition or intestinal diarrhea; and polygenic, such as low plasma amino acid levels that interact with the primary monogenic defect. Males and females are equally affected. Consanguinity in parents and affected siblings occurs not uncommonly. The disorder is worldwide and not associated with other genetic disorders.
The earliest clinical findings are photosensitive skin,
leading to the pellagra-like rash in late infancy or early childhood. Later, episodic neuropsychiatric symptoms appear--intermittent cerebellar ataxia and emotional lability to psychoses--together or separately and often triggered by poor nutrition and diarrhea, fever, or sun exposure. EEGs are nonspecific, and CSF studies are normal. Partial expressions, such as intestinal or renal tubular defects alone, may be seen. The differential diagnosis includes any cause of acute cerebellar ataxia in childhood: postinfectious cerebellitis, brain stem encephalitis, posterior fossa tumor, and vestibular neuronitis. When attacks are intermittent, particularly with the mental symptoms, episodic disturbances such as nonconvulsive status epilepticus, acute confusional migraine, other toxic-metabolic encephalopathies, or demyelinating disease should be considered. The rash with neurological signs should bring to mind other vitamin deficiency diseases, such as thiamine or biotinidase deficiency.
The evaluation involves simple urine amino acid chromatography, which will detect the neutral aminoaciduria, and oral loading tests with L-tryptophan, which will detect the indoluria. No consistent picture of abnormalities has arisen from brain CT, MRI, and PET studies. To treat symptomatic subjects, nicotinamide, rather than nicotinic acid, is given orally at 50 to 300 mg/day. Both the rash and ataxia respond. A high protein diet may help prevent attacks in those with low plasma amino acid resting levels. Although mental retardation may occur, dementia does not. There may be learning difficulties, but most patients have normal mentation. Further specific therapy awaits elucidation of the specific membrane transport carrier system and whether the defect is of transport activation, regulation, or direct transporting, as well as mapping and cloning of the gene. As yet there are no animal models.
Menkes' disease, an X-linked disorder in which insufficient intestinal absorption of copper leads to deficiency of copper-requiring enzymes, is now known to be due to a gene located at Xq13.3. y The gene product belongs to a highly conserved family of cation-transporting ATPases, which function in the transport of ions across cellular and intracellular membranes. The low serum copper levels, the high tissue levels (particularly intestinal mucosa, except liver), and studies from patients' cultured cells strongly suggest that the basic pathogenetic defect is the failure of a plasma membrane pump that usually extrudes copper from cells or the failure of a pump that ordinarily transports copper into an intracellular organelle-like endoplasmic reticulum. Deficient activity of copper-requiring enzymes explains the symptoms and signs. Deficiency of dopamine beta-hydroxylase, critical to the catecholamine synthesis pathway, may be related to autonomic abnormalities due to decreased sympathetic adrenergic function. Cytochrome-c oxidase deficiency probably can be related to hypotonia, weakness, and the lesions similar to those seen in Leigh's disease, without severe lactic acidosis associated with complex IV respiratory chain defects. Reduced lysyl oxidase activity relates to the arterial tortuosity and other connective tissue disorders. Reduced tyrosine hydroxylase leads to lack of pigmentation. Partial loss of copper-zinc superoxide dismutase (Cu-Zn SOD) could lead to oxidant stress and cytotoxicity because of lack of defense against oxygen free radicals. The incidence is estimated to be 1 in 100,000 to 250,000 live births, a rare condition. One third of the estimated 15 to 30 infants born annually in the United States are predicted to be nonfamilial new mutations.
Male infants usually present at 2 to 3 months with developmental arrest and regression, hypotonia, seizures, and failure to thrive. Seizures are an early presentation, are frequent, and are multifocal myoclonic jerks that are often stimulus-precipitated. Recurrent hypothermia and infections occur. The near-pathognomonic clinical sign is scarce, colorless, wiry, friable hair on scalp and eyebrows and, under the microscope, the characteristic appearance of pili torti (twisted hair shaft). Secondary microcephaly occurs later. A mild Menkes' disease variant occurs, with later onset and milder neurological findings. The occipital horn syndrome, another variant, has few mental or neurological signs but calcified occipital horns, changes in clavicles and long bones, and sometimes chronic diarrhea and arterial changes. The differential diagnosis includes any early infantile progressive encephalopathy presenting with seizures, such as storage disease (Tay-Sachs disease, Sandhoff's disease, infantile neuronal ceroid lipofuscinosis), aminoacidurias (nonketotic hyperglycinemia), disorders of biogenic amine metabolism (folinic acid-responsive seizures), mitochondrial diseases (Alpers' disease), sulfite oxidase deficiency, glucose transporter deficiency, or the nonprogressive infantile myoclonic epilepsies. To make the diagnosis, the clinical picture, along with typical radiological features (osteoporosis, scalloping of vertebral bodies, excessive wormian bone formation), microscopic examination of the hair, and very low levels of serum copper and ceruloplasmin after the neonatal period, is sufficient. Cultured skin fibroblasts show increased copper content. In families at risk, prenatal diagnosis and heterozygote carrier detection can be done by biochemical and mutational analysis of cultured amniocytes or chorionic villi. The therapeutic strategies must (1) bypass the block in intestinal copper absorption; (2) supply copper to intracellular enzymes that require it for a cofactor; and (3) identify and treat patients early, preferably presymptomatically. Intravenous copper histidine bypasses the intestinal block but produces no substantive neurological improvement nor increases life span. Therapy with vitamins C and E has been ineffective. Supportive care includes maximizing caloric intake, physical and occupational therapy, psychosocial support of families, and, most importantly, genetic counseling. Children usually die by the age of 3. Future treatments might explore the principle that lipid-soluble complexes can increase copper transport through cellular membranes. Gene therapy would be difficult because of the widespread, multisystem involvement and awaits functional characterization of the transport protein and progress in developing gene delivery systems to the brain.
GLUCOSE TRANSPORTER DEFICIENCY (DEVIVO DISEASE)
The erythrocyte glucose transporter is homologous to that in the brain, with both facilitating the diffusion of glucose across lipophilic plasma membranes. '73! This condition is due to defective functioning of the type 1 glucose
transporter (GLUT1) in brain microvessels at the blood- brain barrier, causing low CSF glucose (hypoglycorrhachia) and therefore decreased cerebral energy metabolism and brain function. GLUT1 is coded by a gene localized to chromosome 1 and is developmentally regulated, with the messenger RNA in brain increasing with increasing cerebral metabolic rate for glucose in infancy and childhood. Symptoms occur when this rate increases in early infancy, doubling or tripling that in the neonatal and fetal periods. This is a very rare condition, probably a spontaneous mutation, with patients being symptomatic heterozygotes.
At about age 3 months, a perfectly normal infant develops seizures--myoclonic, atypical absences, or unclassifiable--that are refractory to antiepileptic drugs. Developmental delay occurs the longer seizures are uncontrolled and the diagnosis is undiscovered, which can culminate in mental retardation and secondary microcephaly. The differential diagnosis includes any disease or condition causing refractory seizures in early infancy (see section on Menkes' disease). In this disorder, CSF glucose is 30 mg/ dl or lower, with a reduced CSF/blood glucose ratio (about 0.33). CSF lactate is also low (0.97 mM/L or less). EEGs and neuroimaging studies are normal. Treatment involves seizure control with a ketogenic diet, because the diet provides ketone bodies as an alternative source of fuel for brain metabolism. The prognosis for seizure control and normal development is excellent, with early diagnosis and treatment. It is likely that the defect becomes less consequential with age as the cerebral metabolic rate for glucose slows down to adult levels.
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