MedGen

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]

Myotonic dystrophy type 1 (DM1) is a multisystem disorder that affects skeletal and smooth muscle as well as the eye, heart, endocrine system, and central nervous system. The clinical findings, which span a continuum from mild to severe, have been categorized into three somewhat overlapping phenotypes: mild, classic, and congenital. Mild DM1 is characterized by cataract and mild myotonia (sustained muscle contraction); life span is normal. Classic DM1 is characterized by muscle weakness and wasting, myotonia, cataract, and often cardiac conduction abnormalities; adults may become physically disabled and may have a shortened life span. Congenital DM1 is characterized by hypotonia and severe generalized weakness at birth, often with respiratory insufficiency and early death; intellectual disability is common. [from GeneReviews]

Prader-Willi syndrome (PWS) is characterized by severe hypotonia and feeding difficulties in early infancy, followed in later infancy or early childhood by excessive eating and gradual development of morbid obesity (unless eating is externally controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. A distinctive behavioral phenotype (with temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone); characteristic facial features, strabismus, and scoliosis are often present. [from GeneReviews]

3-Hydroxy-3-methylglutaryl-CoA lyase deficiency (HMGCLD) is a rare autosomal recessive disorder with the cardinal manifestations of metabolic acidosis without ketonuria, hypoglycemia, and a characteristic pattern of elevated urinary organic acid metabolites, including 3-hydroxy-3-methylglutaric, 3-methylglutaric, and 3-hydroxyisovaleric acids. Urinary levels of 3-methylcrotonylglycine may be increased. Dicarboxylic aciduria, hepatomegaly, and hyperammonemia may also be observed. Presenting clinical signs include irritability, lethargy, coma, and vomiting (summary by Gibson et al., 1988). [from OMIM]

Tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; 612349), tyrosine hydroxylase (TH; 191290) and tryptophan hydroxylase (TPH1; 191060), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (Dudesek et al., 2001). HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (Dudesek et al., 2001). Other forms of BH4-deficient HPA include HPABH4B (233910), caused by mutation in the GCH1 gene (600225), HPABH4C (261630), caused by mutation in the QDPR gene (612676), and HPABH4D (264070), caused by mutation in the PCBD1 gene (126090). Niederwieser et al. (1982) noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; 261600), caused by mutation in the PAH gene. Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (612716), caused by mutation in the SPR gene (182125), and autosomal dominant dopa-responsive dystonia (DYT5; 128230), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed. [from OMIM]

Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is a genetically heterogeneous autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and early death. The phenotype commonly includes cobblestone (type II) lissencephaly, cerebellar malformations, and retinal malformations. More variable features include macrocephaly or microcephaly, hypoplasia of midline brain structures, ventricular dilatation, microphthalmia, cleft lip/palate, and congenital contractures (Dobyns et al., 1989). Those with a more severe phenotype characterized as Walker-Warburg syndrome often die within the first year of life, whereas those characterized as having muscle-eye-brain disease may rarely acquire the ability to walk and to speak a few words. These are part of a group of disorders resulting from defective glycosylation of DAG1 (128239), collectively known as 'dystroglycanopathies' (Godfrey et al., 2007). Genetic Heterogeneity of Congenital Muscular Dystrophy-Dystroglycanopathy with Brain and Eye Anomalies (Type A) Muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A) is genetically heterogeneous and can be caused by mutation in other genes involved in DAG1 glycosylation: see MDDGA2 (613150), caused by mutation in the POMT2 gene (607439); MDDGA3 (253280), caused by mutation in the POMGNT1 gene (606822); MDDGA4 (253800), caused by mutation in the FKTN gene (607440); MDDGA5 (613153), caused by mutation in the FKRP gene (606596); MDDGA6 (613154), caused by mutation in the LARGE gene (603590); MDDGA7 (614643), caused by mutation in the ISPD gene (CRPPA; 614631); MDDGA8 (614830) caused by mutation in the GTDC2 gene (POMGNT2; 614828); MDDGA9 (616538), caused by mutation in the DAG1 gene (128239); MDDGA10 (615041), caused by mutation in the TMEM5 gene (RXYLT1; 605862); MDDGA11 (615181), caused by mutation in the B3GALNT2 gene (610194); MDDGA12 (615249), caused by mutation in the SGK196 gene (POMK; 615247); MDDGA13 (615287), caused by mutation in the B3GNT1 gene (B4GAT1; 605517); and MDDGA14 (615350), caused by mutation in the GMPPB gene (615320). [from OMIM]

Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis. Ophthalmoplegia and sensorineural deafness develop by age seven years. By adolescence, affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident. Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness. [from GeneReviews]

DNMT1-related disorder is a degenerative disorder of the central and peripheral nervous systems comprising a phenotypic spectrum that includes hereditary sensory and autonomic neuropathy type 1E (HSAN1E) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN). DNMT1 disorder is often characterized by moderate-to-severe sensorineural hearing loss beginning in the teens or early 20s, sensory impairment, sudomotor dysfunction (loss of sweating), and dementia usually beginning in the mid-40s. In some affected individuals, narcolepsy/cataplexy syndrome and ataxia are predominant findings. [from GeneReviews]

Adie (1926) first delineated narcolepsy as a separate and specific entity. It is a sleep disorder characterized by attacks of disabling daytime drowsiness and low alertness. The normal physiologic components of rapid eye movement (REM) sleep, dreaming and loss of muscle tone, are separated and also occur while the subject is awake, resulting in half-sleep dreams and episodes of skeletal muscle paralysis and atonia (cataplexy and sleep paralysis). Unlike normal sleep, that of narcolepsy often begins with REM activity and the time taken to fall asleep is shorter than normal. In contrast to animal models, human narcolepsy is not a simple genetic disorder. Most human cases of narcolepsy are sporadic and carry a specific HLA haplotype (Peyron et al., 2000). Familial cases are the exception rather than the rule, and monozygotic twins show only partial concordance (25 to 31%) (Mignot, 1998). Genetic Heterogeneity of Narcolepsy Additional narcolepsy loci have been mapped to chromosomes 4 (NRCLP2; 605841), 21q (NRCLP3; 609039), 22q13 (NRCLP4; 612417), 14q11 (NRCLP5; 612851), and 19p13.2 (NRCLP6; 614223). NRCLP7 (614250) is caused by mutation in the MOG gene (159465) on chromosome 6p22. Resistance to narcolepsy is associated with minor alleles of a SNP and a marker in the NLC1A gene (610259) on chromosome 21q22. [from OMIM]

ADCADN is an autosomal dominant neurologic disorder characterized by adult onset of progressive cerebellar ataxia, narcolepsy/cataplexy, sensorineural deafness, and dementia. More variable features include optic atrophy, sensory neuropathy, psychosis, and depression (summary by Winkelmann et al., 2012). [from OMIM]

Obstructive sleep apnea is a common, chronic, complex disease associated with serious cardiovascular and neuropsychologic sequelae and with substantial social and economic costs (Palmer et al., 2003). [from OMIM]

Dihydropyrimidinase deficiency (DPYSD) is an autosomal recessive disease characterized by the presence of dihydropyrimidinuria. The clinical phenotype is highly variable, ranging from early infantile onset of severe neurologic involvement, dysmorphic features, and feeding problems to late onset of mild intellectual disability and even asymptomatic individuals. Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of the anticancer drug 5-fluorouracil (5-FU) (summary by Nakajima et al., 2017). See also dihydropyrimidine dehydrogenase deficiency (274270), a similar disorder. [from OMIM]

Hypoventilation syndrome in very obese persons with excessive adipose tissue around the abdomen and diaphragm is characterized by diminished to absent ventilatory chemoresponsiveness; chronic hypoxia; hypercapnia; polycythemia; and long periods of sleep during day and night (hypersomnolence). It is a condition often related to obstructive sleep apnea but can occur separately. [from MONDO]

Some people with narcolepsy have all of the major features of the disorder, while others have only one or two. Most of the signs and symptoms persist throughout life, although episodes of cataplexy may become less frequent with age and treatment.

Narcolepsy also affects nighttime sleep. Most affected individuals have trouble sleeping for more than a few hours at night. They often experience vivid hallucinations while falling asleep (hypnogogic hallucinations) or while waking up (hypnopompic hallucinations). Affected individuals often have realistic and distressing dreams, and they may act out their dreams by moving excessively or talking in their sleep. Many people with narcolepsy also experience sleep paralysis, which is an inability to move or speak for a short period while falling asleep or awakening. The combination of hallucinations, vivid dreams, and sleep paralysis is often frightening and unpleasant for affected individuals.

Another common feature of narcolepsy is cataplexy, which is a sudden loss of muscle tone in response to strong emotion (such as laughing, surprise, or anger). These episodes of muscle weakness can cause an affected person to slump over or fall, which occasionally leads to injury. Episodes of cataplexy usually last just a few seconds, and they may occur from several times a day to a few times a year. Most people diagnosed with narcolepsy also have cataplexy. However, some do not, which has led researchers to distinguish two major forms of the condition: narcolepsy with cataplexy and narcolepsy without cataplexy.

Narcolepsy is characterized by excessive daytime sleepiness. Affected individuals feel tired during the day, and several times a day they may experience an overwhelming urge to sleep. "Sleep attacks" can occur at unusual times, such as during a meal or in the middle of a conversation. They last from a few seconds to a few minutes and often lead to a longer nap, after which affected individuals wake up feeling refreshed.

Narcolepsy is a chronic sleep disorder that disrupts the normal sleep-wake cycle. Although this condition can appear at any age, it most often begins in adolescence. [from MedlinePlus Genetics]

Narcolepsy is a chronic sleep disorder that disrupts the normal sleep-wake cycle. Although this condition can appear at any age, it most often begins in adolescence.

Narcolepsy is characterized by excessive daytime sleepiness. Affected individuals feel tired during the day, and several times a day they may experience an overwhelming urge to sleep. "Sleep attacks" can occur at unusual times, such as during a meal or in the middle of a conversation. They last from a few seconds to a few minutes and often lead to a longer nap, after which affected individuals wake up feeling refreshed.

Another common feature of narcolepsy is cataplexy, which is a sudden loss of muscle tone in response to strong emotion (such as laughing, surprise, or anger). These episodes of muscle weakness can cause an affected person to slump over or fall, which occasionally leads to injury. Episodes of cataplexy usually last just a few seconds, and they may occur from several times a day to a few times a year. Most people diagnosed with narcolepsy also have cataplexy. However, some do not, which has led researchers to distinguish two major forms of the condition: narcolepsy with cataplexy and narcolepsy without cataplexy.

Narcolepsy also affects nighttime sleep. Most affected individuals have trouble sleeping for more than a few hours at night. They often experience vivid hallucinations while falling asleep (hypnogogic hallucinations) or while waking up (hypnopompic hallucinations). Affected individuals often have realistic and distressing dreams, and they may act out their dreams by moving excessively or talking in their sleep. Many people with narcolepsy also experience sleep paralysis, which is an inability to move or speak for a short period while falling asleep or awakening. The combination of hallucinations, vivid dreams, and sleep paralysis is often frightening and unpleasant for affected individuals.

Some people with narcolepsy have all of the major features of the disorder, while others have only one or two. Most of the signs and symptoms persist throughout life, although episodes of cataplexy may become less frequent with age and treatment. [from MedlinePlus Genetics]

A state of abnormally strong desire for sleep during the daytime. [from HPO]