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.

Allan-Herndon-Dudley syndrome (AHDS), an X-linked disorder, is characterized in males by neurologic findings (hypotonia and feeding difficulties in infancy, developmental delay / intellectual disability ranging from mild to profound) and later-onset pyramidal signs, extrapyramidal findings (dystonia, choreoathetosis, paroxysmal movement disorder, hypokinesia, masked facies), and seizures, often with drug resistance. Additional findings can include dysthyroidism (manifest as poor weight gain, reduced muscle mass, and variable cold intolerance, sweating, elevated heart rate, and irritability) and pathognomonic thyroid test results. Most heterozygous females are not clinically affected but may have minor thyroid test abnormalities.

Pelizaeus-Merzbacher-like disease 1 (PMLD1) is a slowly progressive leukodystrophy that typically presents during the neonatal or early-infantile period with nystagmus, commonly associated with hypotonia, delayed acquisition of motor milestones, speech delay, and dysarthria. Over time the hypotonia typically evolves into spasticity that affects the ability to walk and communicate. Cerebellar signs (gait ataxia, dysmetria, intention tremor, head titubation, and dysdiadochokinesia) frequently manifest during childhood. Some individuals develop extrapyramidal movement abnormalities (choreoathetosis and dystonia). Hearing loss and optic atrophy are observed in rare cases. Motor impairments can lead to swallowing difficulty and orthopedic complications, including hip dislocation and scoliosis. Most individuals have normal cognitive skills or mild intellectual disability – which, however, can be difficult to evaluate in the context of profound motor impairment.

Classic Joubert syndrome (JS) is characterized by three primary findings: A distinctive cerebellar and brain stem malformation called the molar tooth sign (MTS). Hypotonia. Developmental delays. Often these findings are accompanied by episodic tachypnea or apnea and/or atypical eye movements. In general, the breathing abnormalities improve with age, truncal ataxia develops over time, and acquisition of gross motor milestones is delayed. Cognitive abilities are variable, ranging from severe intellectual disability to normal. Additional findings can include retinal dystrophy, renal disease, ocular colobomas, occipital encephalocele, hepatic fibrosis, polydactyly, oral hamartomas, and endocrine abnormalities. Both intra- and interfamilial variation are seen.

X-linked intellectual disability-retinitis pigmentosa syndrome is characterized by moderate intellectual deficit and severe, early-onset retinitis pigmentosa. It has been described in five males spanning three generations of one family. Some patients also had microcephaly. It is transmitted as an X-linked recessive trait.

Leber congenital amaurosis primarily affects the retina, which is the specialized tissue at the back of the eye that detects light and color. This condition causes vision problems, including an increased sensitivity to light (photophobia), involuntary movements of the eyes (nystagmus), and extreme farsightedness (hyperopia). Some people with Senior-Løken syndrome develop the signs of Leber congenital amaurosis within the first few years of life, while others do not develop vision problems until later in childhood.\n\nNephronophthisis causes fluid-filled cysts to develop in the kidneys beginning in childhood. These cysts impair kidney function, initially causing increased urine production (polyuria), excessive thirst (polydipsia), general weakness, and extreme tiredness (fatigue). Nephronophthisis leads to end-stage renal disease (ESRD) later in childhood or in adolescence. ESRD is a life-threatening failure of kidney function that occurs when the kidneys are no longer able to filter fluids and waste products from the body effectively.\n\nSenior-Løken syndrome is a rare disorder characterized by the combination of two specific features: a kidney condition called nephronophthisis and an eye condition known as Leber congenital amaurosis.

Untreated pyridox(am)ine 5'-phosphate oxidase (PNPO) deficiency, characterized by a range of seizure types, is "classic" (i.e., seizure onset in the neonatal period) in about 90% of affected individuals and "late onset" (seizure onset after the neonatal period) in about 10%. In classic PNPO deficiency, seizures (including status epilepticus) often begin on the first day of life and typically before age two weeks. In both classic and late-onset untreated PNPO deficiency, seizure semiology varies from myoclonic to clonic or tonic seizures, and seizures are typically resistant to common anti-seizure medications. Independent of age of onset, seizures respond to life-long treatment with a B6 vitamer: pyridoxal 5'-phosphate (PLP) in about 60% of affected individuals and pyridoxine (PN) in about 40%. About 60% of individuals with PNPO deficiency have developmental impairment, affecting speech, cognition, and behavior; some individuals have neurologic impairment such as muscular hypotonia or dystonia. Severe neurodevelopmental impairment is more likely to occur in individuals with PNPO deficiency who experienced diagnostic delay and prolonged periods of uncontrolled seizures.

Frontonasal dysplasia-2 (FND2) is an autosomal recessive disorder characterized by variable degrees of alopecia, skull defects, hypertelorism, depressed nasal bridge and ridge with notched alae nasi, and abnormal central nervous system findings (summary by Kariminejad et al., 2014).

Mitochondrial pyruvate carrier deficiency is an autosomal recessive metabolic disorder characterized by delayed psychomotor development and lactic acidosis with a normal lactate/pyruvate ratio resulting from impaired mitochondrial pyruvate oxidation (summary by Bricker et al., 2012).

Meckel syndrome, also known as Meckel-Gruber syndrome, is a severe pleiotropic autosomal recessive developmental disorder caused by dysfunction of primary cilia during early embryogenesis. There is extensive clinical variability and controversy as to the minimum diagnostic criteria. Early reports, including that of Opitz and Howe (1969) and Wright et al. (1994), stated that the classic triad of Meckel syndrome comprises (1) cystic renal disease; (2) a central nervous system malformation, most commonly occipital encephalocele; and (3) polydactyly, most often postaxial. However, based on a study of 67 patients, Salonen (1984) concluded that the minimum diagnostic criteria are (1) cystic renal disease; (2) CNS malformation, and (3) hepatic abnormalities, including portal fibrosis or ductal proliferation. In a review of Meckel syndrome, Logan et al. (2011) stated that the classic triad first described by Meckel (1822) included occipital encephalocele, cystic kidneys, and fibrotic changes to the liver. Genetic Heterogeneity of Meckel Syndrome See also MKS2 (603194), caused by mutation in the TMEM216 gene (613277) on chromosome 11q12; MKS3 (607361), caused by mutation in the TMEM67 gene (609884) on chromosome 8q; MKS4 (611134), caused by mutation in the CEP290 gene (610142) on chromosome 12q; MKS5 (611561), caused by mutation in the RPGRIP1L gene (610937) on chromosome 16q12; MKS6 (612284), caused by mutation in the CC2D2A gene (612013) on chromosome 4p15; MKS7 (267010), caused by mutation in the NPHP3 (608002) gene on chromosome 3q22; MKS8 (613885), caused by mutation in the TCTN2 gene (613846) on chromosome 12q24; MKS9 (614209), caused by mutation in the B9D1 gene (614144) on chromosome 17p11; MKS10 (614175), caused by mutation in the B9D2 gene (611951) on chromosome 19q13; MKS11 (615397), caused by mutation in the TMEM231 gene (614949) on chromosome 16q23; MKS12 (616258), caused by mutation in the KIF14 gene (611279) on chromosome 1q32; MKS13 (617562), caused by mutation in the TMEM107 gene (616183) on chromosome 17p13; and MKS14 (619879), caused by mutation in the TXNDC15 gene (617778) on chromosome 5q31.

Hypomyelinating leukodystrophy-16 is an autosomal dominant neurologic disorder characterized by onset of hypotonia, nystagmus, and mildly delayed motor development in infancy. Affected individuals have motor disabilities, including ataxic or broad-based gait, hyperreflexia, intention tremor, dysmetria, and a mild pyramidal syndrome. Some patients have cognitive impairment, whereas others may have normal cognition or mild intellectual disability with speech difficulties. Brain imaging typically shows hypomyelination, leukodystrophy, and thin corpus callosum (summary by Simons et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of hypomyelinating leukodystrophy, see 312080.

Ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic features (IKSHD) is characterized by epidermal hyperproliferation and increased keratinization, resulting in ichthyosis; hypomyelination of central white matter, causing spastic paraplegia and central nystagmus; and optic atrophy, resulting in reduction of peripheral vision and visual acuity (Mueller et al., 2019). In addition, patients exhibit mild facial dysmorphism (Kutkowska-Kazmierczak et al., 2018).

Retinal dystrophy and leukodystrophy (RDLKD) is a peroxisomal enzyme deficiency caused by impaired very long chain fatty acid (VLCFA) metabolism. Patients exhibit ataxia and spastic paraparesis as well as developmental delay, and may show facial dysmorphism (Ferdinandusse et al., 2017).

Neurodevelopmental disorder with hypotonia, facial dysmorphism, and brain abnormalities (NEDHFBA) is an autosomal recessive neurologic syndrome characterized by global developmental delay with severely impaired intellectual development, hypotonia and muscle weakness, often resulting in the inability to walk or sit, and characteristic coarse facial features. Additional features include feeding difficulties, respiratory distress, scoliosis, poor visual function, and rotary nystagmus. Brain imaging shows variable abnormalities, including enlarged ventricles, decreased white matter volume, white matter changes, thin corpus callosum, and cerebellar hypoplasia (summary by Loddo et al., 2020).

Myoclonic dystonia-34 (DYT34) is an autosomal dominant neurologic disorder characterized by childhood-onset dystonia primarily involving the hands and neck, with a fast tremor with superimposed myoclonus (Balint et al., 2020).