This chapter focuses on homocystinuria caused by cystathionine synthase deficiency, which is a genetically determined inborn error of methionine transsulfuration characterized clinically by typical features and biochemically by an excess of homocystine–homocysteine in plasma and urine, and of methionine in plasma. The term homocystinuria indicates a biochemical abnormality and not a specific symptom, syndrome, or enzymatic defect. Mental retardation is the most common neurologic manifestation of cystathionine synthase deficiency. Mild clinical forms of cystathionine synthase deficiency are found in individuals with genetic heterogeneity. Developmental delay, one of the first signs of cystathionine synthase deficiency, is detectable in the first months of life. The intelligence quotient of patients with homocystinuria, when studied in large groups, usually ranged between 30 and 70. Seizures frequently occur in patients with cystathionine synthase deficiency. Clinical eye findings are ectopia lentis, myopia, glaucoma, buphthalmos, staphyloma, cataract, retinal detachment, and optic atrophy. Thromboembolism and its manifestations represent the major clinicopathologic complications of cystathionine synthase deficiency. The palliative treatments of the clinical manifestations of cystathionine synthase deficiency are quite extensive, and include ophthalmologic and orthopedic procedures.

This chapter focuses on Coffin–Siris syndrome. This syndrome is characterized by defects in the skin, hair, brain, cerebellum, brain stem nuclei, and the nails and skeleton of fifth digits. Consistent features include developmental delay, abnormal facies, absent fifth distal phalanx, hypoplastic nails, hypotonia, and body hypertrichosis. Very common features are postnatal growth deficiency, feeding difficulties, microcephaly, and scalp hypotrichosis. The genetics of the Coffin–Siris syndrome continue to be of major interest. One phenotypically similar patient has been described with partial trisomy 9. In cases of Coffin–Siris syndrome, no chromosomal abnormalities have been described despite the suggestions about its inheritance patterns. The genetics of the Coffin–Siris syndrome continue to be of major interest. Only with careful clinical descriptions correlated with well-documented neuropathologic material and genetic studies can this syndrome be better understood. At present, there is no specific therapy and management is only symptomatic.

This chapter focuses on adrenoleukodystrophy (ALD), which is a genetically determined disorder associated with progressive demyelination and adrenal cortical insufficiency. ALD is expressed clinically by varying combinations of dysfunction in the central and peripheral nervous systems, and in the endocrine system. The biochemical testing for ALD seems appropriate for all newly diagnosed males with Addison's disease to discover those that may be manifestations of ALD. Routine X-rays of the skull are normal. Electroencephalograms demonstrate frequency slowing and amplitude reduction maximal in the parietooccipital region in typical childhood ALD. The accumulation of saturated unbranched very long chain fatty acids, particularly hexacosanoate (C26:0), has been demonstrated in all ALD patients and is nearly unique for this disorder.

This chapter focuses on Klippel–Trenaunay syndrome (KTS), which is a congenital anomaly of skin, underlying soft tissue, blood vessels, and bone. The typical findings are angiomatous skin nevus, bony hypertrophy, lymphangioma, or varicosities. Among the neurologic manifestations is mental retardation, found only in patients with face and head hemangiomas, most of whom also have Sturge–Weber syndrome. In patients with leg length discrepancy, scanograms are indicated to determine its degree and to allow judgments to be made about the best time for epiphyseal stapling procedures. With light microscopy, the findings are those of capillary or cavernous hemangiomas. There are no specific morphological changes for KTS. Sturge–Weber syndrome consists of the characteristic unilateral or bilateral nevus angiomatosus of the face, buphthalmos or glaucoma, and meningocortical angiomatosis.

This chapter focuses on hypomelanosis of Ito (HI). Ito in 1952 described a new neurocutaneous entity under the name incontinentia pigmenti achromians, which was subsequently also known by the names systematized achromic nevus or hypomelanosis of Ito. The number of patients with this disorder reported to date is a very small proportion of the existing cases. HI is one of the most common neurocutaneous disorders associated with melanin disturbance. There is no known racial predominance of HI although recently a large number of nonwhite individuals were reported. This might be because of a high prevalence of black individuals in the population studied. The disorder is said to be more prevalent in females than males. The hereditary nature of HI is as yet unclear. It appears that in some families there is an autosomal dominant transmission. In other cases, the hereditary nature is obscure and could be explained if one admits the existence of minisymptomatic forms or formes frustes and asymptomatic carriers—that is, a clinically unaffected descendant of a patient passing it on to a subsequent descendant. There is no treatment for the hypomelanosis of the skin.

This chapter discusses Refsum's disease, which is a biochemically well-defined disease for which there is a specific dietary treatment. The disease is characterized by pigmentary retinal degeneration—retinitis pigmentosa—chronic polyneuropathy, ataxia, and an increase in cerebrospinal fluid protein with normal cell content. Ataxia and other cerebellar signs have been prominent in many cases, and sometimes, unsteadiness of gait has been the only presenting symptom. Many patients with Refsum's disease experience skin changes. Only a few histologic examinations of the skin in Refsum's disease have been reported. The keratinization disturbance in Refsum's disease has been investigated by Anton–Lamprecht and Kahlke by means of electron microscopy and compared to the keratinization pattern of the common inherited ichthyoses. The diagnosis is based on the clinical picture, the demonstration of an increased level of phytanic acid in serum, and a decreased capacity for α-oxidation of phytanic acid.

This chapter focuses on biochemical role of biotin that is necessary to understand the clinical manifestations of the biotin-responsive diseases. The biotin-responsive multiple carboxylase deficiencies are a group of metabolic disorders whose clinical features include a skin rash and striking neurologic signs. Biotin is widely distributed in most foods, with relatively high concentrations found in liver, egg yolk, cooked grains, cow's milk, and human milk; it is also synthesized by intestinal flora. Biotin-responsive diseases present with one of several clinical patterns, depending upon the specific pathophysiologic mechanisms involved, but the signs usually reflect defective carboxylase activity. Neonatal multiple carboxylase deficiency typically presents in the first several days of life, heralded by vomiting and lethargy. Dietary biotin deficiency most often occurs in patients who have had major segments of their small intestine removed and who are on total parenteral alimentation without supplemental biotin. Dietary biotin deficiency is almost solely restricted to patients with severe gastrointestinal disease on total parenteral nutrition.

This chapter discusses Fabry–Anderson disease (FAD), which is an X-linked glycolipid lysosomal storage disorder that is caused by an alpha-galactosidase deficiency. The unusual array of mostly nonspecific symptoms by which FAD may express itself explains why these historical difficulties are still extant for the clinician who needs to distinguish a rare disorder under commonplace manifestations. FAD is a chronic malady with lifelong, mostly nonspecific manifestations. The first symptom of FAD is generally a bout of excruciating burning pain in the extremities. Clinical signs of peripheral neuropathy are not a feature of FAD. Because globoside, the major erythrocyte glycolipid, is an important source of ceramide trihexoside during the degradation of aging cells, one would expect that the reticuloendothelial system is heavily involved, as is the rule in the multisystemic storage disorders.

This chapter presents a case study on three male patients in a family with congenital anosmia, ichthyosis, and hypogonadotropic hypogonadism. All three patients had borderline IQs, mirror movements of the hands and feet, and ocular manifestations that included congenital nystagmus, strabismus, hypoplastic optic discs with decreased visual acuity, and hypopigmentation of the irides. Two patients had unilateral renal agenesis or hypogenesis and one patient had preauricular pits. Enzymatic study of the leukocytes and skin fibroblasts revealed steroid sulfatase and arylsulfatase C deficiencies. It was seen that ichthyosis was generalized with large dark scales present over the surface of the skin except on the palms and soles. It was noted during the first week of life, increased with age, and worsened in winter. Skin pathology disclosed marked hyperkeratosis and an increased granular layer. Congenital ichthyosis, hypogonadism, and anosmia have been seen as a part of various syndromes. Patients with multiple sulfatase deficiency are frequently associated with ichthyosis.

This chapter discusses citrullinemia and arginosuccinicaciduria. They represent two metabolic disorders resulting from enzymatic impairment in steps 3 and 4 of the urea cycle. Deficiency in arginosuccinic acid synthetase causes a metabolic disorder characterized by a markedly elevated plasma citrulline level and an elevated plasma ammonia concentration without acidosis. An infant with arginosuccinicaciduria, as with citrullinemia, is normal at birth and then exhibits symptoms 24–48 hours after birth. In approximately one-half of patients with the subacute or late-onset form of arginosuccinicaciduria, a type of abnormal hair, trichorrhexis nodosa, is seen. Treatment of citrullinemia and arginosuccinicaciduria, as with other urea cycle disorders, consists of prevention of hyperammonemic events, and treatment of episodic hyperammonemia and acute hyperammonemic coma. Prognosis, especially in the neonatal form of the urea cycle disorders, has been extremely poor.