MedGen

If untreated, young children with profound biotinidase deficiency usually exhibit neurologic abnormalities including seizures, hypotonia, ataxia, developmental delay, vision problems, hearing loss, and cutaneous abnormalities (e.g., alopecia, skin rash, candidiasis). Older children and adolescents with profound biotinidase deficiency often exhibit motor limb weakness, spastic paresis, and decreased visual acuity. Once vision problems, hearing loss, and developmental delay occur, they are usually irreversible, even with biotin therapy. Individuals with partial biotinidase deficiency may have hypotonia, skin rash, and hair loss, particularly during times of stress. [from GeneReviews]

Ornithine transcarbamylase (OTC) deficiency can occur as a severe neonatal-onset disease in males (but rarely in females) and as a post-neonatal-onset (also known as "late-onset" or partial deficiency) disease in males and females. Males with severe neonatal-onset OTC deficiency are asymptomatic at birth but become symptomatic from hyperammonemia in the first week of life, most often on day two to three of life, and are usually catastrophically ill by the time they come to medical attention. After successful treatment of neonatal hyperammonemic coma these infants can easily become hyperammonemic again despite appropriate treatment; they typically require liver transplant to improve quality of life. Males and heterozygous females with post-neonatal-onset (partial) OTC deficiency can present from infancy to later childhood, adolescence, or adulthood. No matter how mild the disease, a hyperammonemic crisis can be precipitated by stressors and become a life-threatening event at any age and in any situation in life. For all individuals with OTC deficiency, typical neuropsychological complications include developmental delay, learning disabilities, intellectual disability, attention-deficit/hyperactivity disorder, and executive function deficits. [from GeneReviews]

Citrullinemia type I (CTLN1) presents as a spectrum that includes a neonatal acute form (the "classic" form), a milder late-onset form (the "non-classic" form), a form in which women have onset of symptoms at pregnancy or post partum, and a form without symptoms or hyperammonemia. Distinction between the forms is based primarily on clinical findings, although emerging evidence suggests that measurement of residual argininosuccinate synthase enzyme activity may help to predict those who are likely to have a severe phenotype and those who are likely to have an attenuated phenotype. Infants with the acute neonatal form appear normal at birth. Shortly thereafter, they develop hyperammonemia and become progressively lethargic, feed poorly, often vomit, and may develop signs of increased intracranial pressure (ICP). Without prompt intervention, hyperammonemia and the accumulation of other toxic metabolites (e.g., glutamine) result in increased ICP, increased neuromuscular tone, spasticity, ankle clonus, seizures, loss of consciousness, and death. Children with the severe form who are treated promptly may survive for an indeterminate period of time, but usually with significant neurologic deficits. Even with chronic protein restriction and scavenger therapy, long-term complications such as liver failure and other (rarely reported) organ system manifestations are possible. The late-onset form may be milder than that seen in the acute neonatal form, but commences later in life for reasons that are not completely understood. The episodes of hyperammonemia are similar to those seen in the acute neonatal form, but the initial neurologic findings may be more subtle because of the older age of the affected individuals. Women with onset of severe symptoms including acute hepatic decompensation during pregnancy or in the postpartum period have been reported. Furthermore, previously asymptomatic and non-pregnant individuals have been described who remained asymptomatic up to at least age ten years, with the possibility that they could remain asymptomatic lifelong. [from GeneReviews]

Arginase deficiency in untreated individuals is characterized by episodic hyperammonemia of variable degree that is infrequently severe enough to be life threatening or to cause death. Most commonly, birth and early childhood are normal. Untreated individuals have slowing of linear growth at age one to three years, followed by development of spasticity, plateauing of cognitive development, and subsequent loss of developmental milestones. If untreated, arginase deficiency usually progresses to severe spasticity, loss of ambulation, complete loss of bowel and bladder control, and severe intellectual disability. Seizures are common and are usually controlled easily. Individuals treated from birth, either as a result of newborn screening or having an affected older sib, appear to have minimal symptoms. [from GeneReviews]

Homocystinuria caused by cystathionine ß-synthase (CBS) deficiency is characterized by involvement of the eye (ectopia lentis and/or severe myopia), skeletal system (excessive height, long limbs, scolioisis, and pectus excavatum), vascular system (thromboembolism), and CNS (developmental delay/intellectual disability). All four ? or only one ? of the systems can be involved; expressivity is variable for all of the clinical signs. It is not unusual for a previously asymptomatic individual to present in adult years with only a thromboembolic event that is often cerebrovascular. Two phenotypic variants are recognized, B6-responsive homocystinuria and B6-non-responsive homocystinuria. B6-responsive homocystinuria is usually milder than the non-responsive variant. Thromboembolism is the major cause of early death and morbidity. IQ in individuals with untreated homocystinuria ranges widely, from 10 to 138. In B6-responsive individuals the mean IQ is 79 versus 57 for those who are B6-non-responsive. Other features that may occur include: seizures, psychiatric problems, extrapyramidal signs (e.g., dystonia), hypopigmentation of the skin and hair, malar flush, livedo reticularis, and pancreatitis. [from GeneReviews]

Deficiency of argininosuccinate lyase (ASL), the enzyme that cleaves argininosuccinic acid to produce arginine and fumarate in the fourth step of the urea cycle, may present as a severe neonatal-onset form or a late-onset form: The severe neonatal-onset form is characterized by hyperammonemia within the first few days after birth that can manifest as increasing lethargy, somnolence, refusal to feed, vomiting, tachypnea, and respiratory alkalosis. Absence of treatment leads to worsening lethargy, seizures, coma, and even death. In contrast, the manifestations of late-onset form range from episodic hyperammonemia triggered by acute infection or stress to cognitive impairment, behavioral abnormalities, and/or learning disabilities in the absence of any documented episodes of hyperammonemia. Manifestations of ASL deficiency that appear to be unrelated to the severity or duration of hyperammonemic episodes: Neurocognitive deficiencies (attention-deficit/hyperactivity disorder, developmental delay, seizures, and learning disability). Liver disease (hepatitis, cirrhosis). Trichorrhexis nodosa (coarse brittle hair that breaks easily). Systemic hypertension. [from GeneReviews]

Mucopolysaccharidosis type I (MPS I) is a progressive multisystem disorder with features ranging over a continuum of severity. While affected individuals have traditionally been classified as having one of three MPS I syndromes (Hurler syndrome, Hurler-Scheie syndrome, or Scheie syndrome), no easily measurable biochemical differences have been identified and the clinical findings overlap. Affected individuals are best described as having either a phenotype consistent with either severe (Hurler syndrome) or attenuated MPS I, a distinction that influences therapeutic options. Severe MPS I. Infants appear normal at birth. Typical early manifestations are nonspecific (e.g., umbilical or inguinal hernia, frequent upper respiratory tract infections before age 1 year). Coarsening of the facial features may not become apparent until after age one year. Gibbus deformity of the lower spine is common and often noted within the first year. Progressive skeletal dysplasia (dysostosis multiplex) involving all bones is universal, as is progressive arthropathy involving most joints. By age three years, linear growth decreases. Intellectual disability is progressive and profound but may not be readily apparent in the first year of life. Progressive cardiorespiratory involvement, hearing loss, and corneal clouding are common. Without treatment, death (typically from cardiorespiratory failure) usually occurs within the first ten years of life. Attenuated MPS I. Clinical onset is usually between ages three and ten years. The severity and rate of disease progression range from serious life-threatening complications leading to death in the second to third decade, to a normal life span complicated by significant disability from progressive joint manifestations and cardiorespiratory disease. While some individuals have no neurologic involvement and psychomotor development may be normal in early childhood, learning disabilities and psychiatric manifestations can be present later in life. Hearing loss, cardiac valvular disease, respiratory involvement, and corneal clouding are common. [from GeneReviews]

Epimerase deficiency galactosemia (GALE deficiency galactosemia) is generally considered a continuum comprising several forms: Generalized. Enzyme activity is profoundly decreased in all tissues tested. Peripheral. Enzyme activity is deficient in red blood cells (RBC) and circulating white blood cells, but normal or near normal in all other tissues. Intermediate. Enzyme activity is deficient in red blood cells and circulating white blood cells and less than 50% of normal levels in other cells tested. Infants with generalized epimerase deficiency galactosemia develop clinical findings on a regular milk diet (which contains lactose, a disaccharide of galactose and glucose); manifestations include hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Prompt removal of galactose/lactose from their diet resolves or prevents these acute symptoms. Longer-term features that may be seen in those with generalized epimerase deficiency include short stature, developmental delay, sensorineural hearing loss, and skeletal anomalies. In contrast, neonates with the peripheral or intermediate form generally remain clinically well even on a regular milk diet and are usually only identified by biochemical testing, often in newborn screening programs. [from GeneReviews]

Barth syndrome is characterized in affected males by cardiomyopathy, neutropenia, skeletal myopathy, prepubertal growth delay, and distinctive facial gestalt (most evident in infancy); not all features may be present in a given affected male. Cardiomyopathy, which is almost always present before age five years, is typically dilated cardiomyopathy with or without endocardial fibroelastosis or left ventricular noncompaction; hypertrophic cardiomyopathy can also occur. Heart failure is a significant cause of morbidity and mortality; risk of arrhythmia and sudden death is increased. Neutropenia is most often associated with mouth ulcers, pneumonia, and sepsis. The nonprogressive myopathy predominantly affects the proximal muscles, and results in early motor delays. Prepubertal growth delay is followed by a postpubertal growth spurt with remarkable "catch-up" growth. Heterozygous females who have a normal karyotype are asymptomatic and have normal biochemical studies. [from GeneReviews]

The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Individuals with late-onset PA may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy. Isolated cardiomyopathy can be observed on rare occasion in the absence of clinical metabolic decompensation or neurocognitive deficits. Manifestations of neonatal and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure. [from GeneReviews]

The phenotype of acid sphingomyelinase deficiency (ASMD) occurs along a continuum. Individuals with the severe early-onset form, infantile neurovisceral ASMD, were historically diagnosed with Niemann-Pick disease type A (NPD-A). The later-onset, chronic visceral form of ASMD is also referred to as Niemann-Pick disease type B (NPD-B). A phenotype with intermediate severity is also known as chronic neurovisceral ASMD (NPD-A/B). The most common presenting symptom in NPD-A is hepatosplenomegaly, usually detectable by age three months; over time the liver and spleen become massive in size. Psychomotor development progresses no further than the 12-month level, after which neurologic deterioration is relentless. Failure to thrive typically becomes evident by the second year of life. A classic cherry-red spot of the macula of the retina, which may not be present in the first few months, is eventually present in all affected children. Interstitial lung disease caused by storage of sphingomyelin in pulmonary macrophages results in frequent respiratory infections and often respiratory failure. Most children succumb before the third year of life. NPD-B generally presents later than NPD-A, and the manifestations are less severe. NPD-B is characterized by progressive hepatosplenomegaly, gradual deterioration in liver and pulmonary function, osteopenia, and atherogenic lipid profile. No central nervous system (CNS) manifestations occur. Individuals with NPD-A/B have symptoms that are intermediate between NPD-A and NPD-B. The presentation in individuals with NPD-A/B varies greatly, although all are characterized by the presence of some CNS manifestations. Survival to adulthood can occur in individuals with NPD-B and NPD-A/B. [from GeneReviews]

Shwachman-Diamond syndrome (SDS) is characterized by: exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplasia syndrome (MDS) and acute myelogeneous leukemia (AML); and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is a common presenting finding, often before the diagnosis of SDS is made. Short stature and recurrent infections are common. [from GeneReviews]

PMM2-CDG, the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides, is divided into three clinical stages: infantile multisystem, late-infantile and childhood ataxia–intellectual disability, and adult stable disability. The clinical manifestations and course are highly variable, ranging from infants who die in the first year of life to mildly affected adults. Clinical findings tend to be similar in sibs. In the infantile multisystem presentation, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay. Feeding problems, vomiting, faltering growth, and developmental delay are frequently seen. Subcutaneous fat may be excessive over the buttocks and suprapubic region. Two distinct clinical courses are observed: (1) a nonfatal neurologic course with faltering growth, strabismus, developmental delay, cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade; and (2) a more severe neurologic-multivisceral course with approximately 20% mortality in the first year of life. The late-infantile and childhood ataxia–intellectual disability stage, which begins between ages three and ten years, is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70; other findings include seizures, stroke-like episodes or transient unilateral loss of function, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities. In the adult stable disability stage, intellectual ability is stable; peripheral neuropathy is variable, progressive retinitis pigmentosa and myopia are seen, thoracic and spinal deformities with osteoporosis worsen, and premature aging is observed; females may lack secondary sexual development and males may exhibit decreased testicular volume. Hypogonadotropic hypogonadism and coagulopathy may occur. The risk for deep venous thrombosis is increased. [from GeneReviews]

Systemic primary carnitine deficiency (CDSP) is a disorder of the carnitine cycle that results in defective fatty acid oxidation. It encompasses a broad clinical spectrum including the following: Metabolic decompensation in infancy typically presenting between age three months and two years with episodes of hypoketotic hypoglycemia, poor feeding, irritability, lethargy, hepatomegaly, elevated liver transaminases, and hyperammonemia triggered by fasting or common illnesses such as upper respiratory tract infection or gastroenteritis. Childhood myopathy involving heart and skeletal muscle with onset between age two and four years. Pregnancy-related decreased stamina or exacerbation of cardiac arrhythmia. Fatigability in adulthood. Absence of symptoms. The latter two categories often include mothers diagnosed with CDSP after newborn screening has identified low carnitine levels in their infants. [from GeneReviews]

Disorders of intracellular cobalamin metabolism have a variable phenotype and age of onset that are influenced by the severity and location within the pathway of the defect. The prototype and best understood phenotype is cblC; it is also the most common of these disorders. The age of initial presentation of cblC spans a wide range: In utero with fetal presentation of nonimmune hydrops, cardiomyopathy, and intrauterine growth restriction. Newborns, who can have microcephaly, poor feeding, and encephalopathy. Infants, who can have poor feeding and slow growth, neurologic abnormality, and, rarely, hemolytic uremic syndrome (HUS). Toddlers, who can have poor growth, progressive microcephaly, cytopenias (including megaloblastic anemia), global developmental delay, encephalopathy, and neurologic signs such as hypotonia and seizures. Adolescents and adults, who can have neuropsychiatric symptoms, progressive cognitive decline, thromboembolic complications, and/or subacute combined degeneration of the spinal cord. [from GeneReviews]

Leigh syndrome is a clinical diagnosis based primarily on characteristic brain imaging findings associated with progressive and severe neurodegenerative features with onset within the first months or years of life, sometimes resulting in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation (summary by Lake et al., 2015). Genetic Heterogeneity of Nuclear Leigh Syndrome Leigh syndrome is a presentation of numerous genetic disorders resulting from defects in the mitochondrial OXPHOS complex. Accordingly, the genes implicated in Leigh syndrome most commonly encode structural subunits of the OXPHOS complex or proteins required for their assembly, stability, and activity. Mutations in both nuclear and mitochondrial genes have been identified. For a discussion of genetic heterogeneity of mitochondrial Leigh syndrome, see MILS (500017). Nuclear Leigh syndrome can be caused by mutations in nuclear-encoded genes involved in any of the mitochondrial respiratory chain complexes: complex I deficiency (see 252010), complex II deficiency (see 252011), complex III deficiency (see 124000), complex IV deficiency (cytochrome c oxidase; see 220110), and complex V deficiency (see 604273) (summary by Lake et al., 2015). Some forms of combined oxidative phosphorylation deficiency (COXPD) can present as Leigh syndrome (see, e.g., 617664). Leigh syndrome may also be caused by mutations in components of the pyruvate dehydrogenase complex (e.g., DLD, 238331 and PDHA1, 300502). Deficiency of coenzyme Q10 (607426) can present as Leigh syndrome. [from OMIM]

PLP1 disorders of central nervous system myelin formation include a range of phenotypes from Pelizaeus-Merzbacher disease (PMD) to spastic paraplegia 2 (SPG2). PMD typically manifests in infancy or early childhood with nystagmus, hypotonia, and cognitive impairment; the findings progress to severe spasticity and ataxia. Life span is shortened. SPG2 manifests as spastic paraparesis with or without CNS involvement and usually normal life span. Intrafamilial variation of phenotypes can be observed, but the signs are usually fairly consistent within families. Heterozygous females may manifest mild-to-moderate signs of the disease. [from GeneReviews]

Alpha-mannosidosis encompasses a continuum of clinical findings from mild to severe. Three major clinical subtypes have been suggested: A mild form recognized after age ten years with absence of skeletal abnormalities, myopathy, and slow progression (type 1). A moderate form recognized before age ten years with presence of skeletal abnormalities, myopathy, and slow progression (type 2). A severe form manifested as prenatal loss or early death from progressive central nervous system involvement or infection (type 3). Individuals with a milder phenotype have mild-to-moderate intellectual disability, impaired hearing, characteristic coarse features, clinical or radiographic skeletal abnormalities, immunodeficiency, and primary central nervous system disease – mainly cerebellar involvement causing ataxia. Periods of psychiatric symptoms are common. Associated medical problems can include corneal opacities, hepatosplenomegaly, aseptic destructive arthritis, and metabolic myopathy. Alpha-mannosidosis is insidiously progressive; some individuals may live into the sixth decade. [from GeneReviews]

Carbamoyl phosphate synthetase I deficiency is an autosomal recessive inborn error of metabolism of the urea cycle which causes hyperammonemia. There are 2 main forms: a lethal neonatal type and a less severe, delayed-onset type (summary by Klaus et al., 2009). Urea cycle disorders are characterized by the triad of hyperammonemia, encephalopathy, and respiratory alkalosis. Five disorders involving different defects in the biosynthesis of the enzymes of the urea cycle have been described: ornithine transcarbamylase deficiency (311250), carbamyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, or citrullinemia (215700), argininosuccinate lyase deficiency (207900), and arginase deficiency (207800). [from OMIM]

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) is one of the enzymes involved in mitochondrial fatty acid ß-oxidation. Fatty acid ß-oxidation fuels hepatic ketogenesis, which provides a major source of energy once hepatic glycogen stores become depleted during prolonged fasting and periods of higher energy demands. MCAD deficiency is the most common disorder of fatty acid ß-oxidation and one of the most common inborn errors of metabolism. Most children are now diagnosed through newborn screening. Clinical symptoms in a previously apparently healthy child with MCAD deficiency include hypoketotic hypoglycemia and vomiting that may progress to lethargy, seizures, and coma triggered by a common illness. Hepatomegaly and liver disease are often present during an acute episode. Children appear normal at birth and – if not identified through newborn screening – typically present between age three and 24 months, although presentation even as late as adulthood is possible. The prognosis is excellent once the diagnosis is established and frequent feedings are instituted to avoid any prolonged periods of fasting. [from GeneReviews]