The spectrum of MECP2-related phenotypes in females ranges from classic Rett syndrome to variant Rett syndrome with a broader clinical phenotype (either milder or more severe than classic Rett syndrome) to mild learning disabilities; the spectrum in males ranges from severe neonatal encephalopathy to pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome to severe syndromic/nonsyndromic intellectual disability. Females: Classic Rett syndrome, a progressive neurodevelopmental disorder primarily affecting girls, is characterized by apparently normal psychomotor development during the first six to 18 months of life, followed by a short period of developmental stagnation, then rapid regression in language and motor skills, followed by long-term stability. During the phase of rapid regression, repetitive, stereotypic hand movements replace purposeful hand use. Additional findings include fits of screaming and inconsolable crying, autistic features, panic-like attacks, bruxism, episodic apnea and/or hyperpnea, gait ataxia and apraxia, tremors, seizures, and acquired microcephaly. Males: Severe neonatal-onset encephalopathy, the most common phenotype in affected males, is characterized by a relentless clinical course that follows a metabolic-degenerative type of pattern, abnormal tone, involuntary movements, severe seizures, and breathing abnormalities. Death often occurs before age two years.

Cronkhite-Canada syndrome is characterized by gastrointestinal hamartomatous polyposis, alopecia, onychodystrophy, skin hyperpigmentation, and diarrhea. It is associated with high morbidity (summary by Sweetser et al., 2012).

An autosomal recessive condition caused by mutation(s) in the ERCC4 gene, encoding DNA repair endonuclease XPF. it is characterized by characterized by cutaneous photosensitivity and progeroid features in multiple organ systems.

Four phenotypes comprise the RRM2B mitochondrial DNA maintenance defects (RRM2B-MDMDs): RRM2B encephalomyopathic MDMD, the most severe phenotype, usually manifesting shortly after birth as hypotonia, poor feeding, and faltering growth requiring hospitalization. Subsequent assessments are likely to reveal multisystem involvement including sensorineural hearing loss, renal tubulopathy, and respiratory failure. Autosomal dominant progressive external ophthalmoplegia (adPEO), typically adult onset; other manifestations can include ptosis, bulbar dysfunction, fatigue, and muscle weakness. RRM2B autosomal recessive progressive external ophthalmoplegia (arPEO), a typically childhood-onset predominantly myopathic phenotype of PEO, ptosis, proximal muscle weakness, and bulbar dysfunction. RRM2B mitochondrial neurogastrointestinal encephalopathy (MNGIE)-like, characterized by progressive ptosis, ophthalmoplegia, gastrointestinal dysmotility, cachexia, and peripheral neuropathy. To date, 78 individuals from 52 families with a molecularly confirmed RRM2B-MDMD have been reported.

POLG-related disorders comprise a continuum of overlapping phenotypes that were clinically defined long before their molecular basis was known. Most affected individuals have some, but not all, of the features of a given phenotype; nonetheless, the following nomenclature can assist the clinician in diagnosis and management. Onset of the POLG-related disorders ranges from infancy to late adulthood. Alpers-Huttenlocher syndrome (AHS), one of the most severe phenotypes, is characterized by childhood-onset progressive and ultimately severe encephalopathy with intractable epilepsy and hepatic failure. Childhood myocerebrohepatopathy spectrum (MCHS) presents between the first few months of life and about age three years with developmental delay or dementia, lactic acidosis, and a myopathy with failure to thrive. Other findings can include liver failure, renal tubular acidosis, pancreatitis, cyclic vomiting, and hearing loss. Myoclonic epilepsy myopathy sensory ataxia (MEMSA) now describes the spectrum of disorders with epilepsy, myopathy, and ataxia without ophthalmoplegia. MEMSA now includes the disorders previously described as spinocerebellar ataxia with epilepsy (SCAE). The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO). About 90% of persons in the ANS have ataxia and neuropathy as core features. Approximately two thirds develop seizures and almost one half develop ophthalmoplegia; clinical myopathy is rare. Autosomal recessive progressive external ophthalmoplegia (arPEO) is characterized by progressive weakness of the extraocular eye muscles resulting in ptosis and ophthalmoparesis (or paresis of the extraocular muscles) without associated systemic involvement; however, caution is advised because many individuals with apparently isolated arPEO at the onset develop other manifestations of POLG-related disorders over years or decades. Of note, in the ANS spectrum the neuropathy commonly precedes the onset of PEO by years to decades. Autosomal dominant progressive external ophthalmoplegia (adPEO) typically includes a generalized myopathy and often variable degrees of sensorineural hearing loss, axonal neuropathy, ataxia, depression, parkinsonism, hypogonadism, and cataracts (in what has been called "chronic progressive external ophthalmoplegia plus," or "CPEO+").

Parkinson disease-23 (PARK23) is a progressive neurodegenerative disorder characterized by young-adult onset of parkinsonism associated with progressive cognitive impairment leading to dementia and dysautonomia. Some individuals have additional motor abnormalities. Affected individuals become severely disabled within a few decades (summary by Lesage et al., 2016).

UNC80 deficiency is characterized by hypotonia, strabismus, oral motor dysfunction, postnatal growth deficiency, and developmental delay. The majority of individuals do not learn to walk. All individuals lack expressive language; however, many have expressive body language, and a few have used signs to communicate. Seizures may develop during infancy or childhood. Additional features can include nystagmus, extremity hypertonia, a high-pitched cry, repetitive and self-stimulatory behaviors, constipation, clubfeet, joint contractures, and scoliosis. For most individuals the UNC80 deficiency syndrome is not progressive. Individuals have slow acquisition of skills and do not have a loss of skills suggestive of neurodegeneration.

Mitochondrial neurogastrointestinal encephalopathy (MNGIE) disease is characterized by progressive gastrointestinal dysmotility (manifesting as early satiety, nausea, dysphagia, gastroesophageal reflux, postprandial emesis, episodic abdominal pain and/or distention, and diarrhea); cachexia; ptosis/ophthalmoplegia or ophthalmoparesis; leukoencephalopathy; and demyelinating peripheral neuropathy (manifesting as paresthesias (tingling, numbness, and pain) and symmetric and distal weakness more prominently affecting the lower extremities). The order in which manifestations appear is unpredictable. Onset is usually between the first and fifth decades; in about 60% of individuals, symptoms begin before age 20 years.

Spinocerebellar ataxia-48 (SCA48) is an autosomal dominant neurodegenerative disorder characterized by onset of gait ataxia and/or cognitive-affective symptoms in midadulthood. Patients may present with involvement of either system, but most eventually develop impairment in both. Features include gait ataxia, dysarthria, and dysphagia, as well as cognitive decline, deficits in executive function, and psychiatric or affective manifestations, such as depression, anxiety, and apathy. Additional more variable features may include movement abnormalities, such as parkinsonism, tremor, chorea, dystonia, and dysmetria; spasticity is not observed. Brain imaging shows selective atrophy of the posterior areas of the cerebellar vermis, often with bilateral T2-weighted hyperintensities in the dentate nuclei (the 'crab sign'), and diffusion tensor imaging (DTI) may show paucity of cerebellar connections to the brainstem and cerebrum. The presentation is consistent with a clinical diagnosis of cerebellar cognitive-affective syndrome (CCAS). The phenotype shows both inter- and intrafamilial variability as well as some clinical overlap with SCAR16, suggesting that mutations in the STUB1 gene result in a spectrum of neurodegenerative manifestations (summary by Genis et al., 2018; Cocozza et al., 2020; Palvadeau et al., 2020; Ravel et al., 2021). Magri et al. (2022) found evidence that heterozygous STUB1 variants alone do not cause disease but require a concurrent expanded repeat allele of the TBP gene (600075) for disease manifestation; see MOLECULAR GENETICS.

Congenital hypomyelinating neuropathy-3 is an autosomal recessive neurologic disorder characterized by onset of neurogenic muscle impairment in utero. Affected individuals present at birth with severe hypotonia, often causing respiratory insufficiency or failure and inability to swallow or feed properly. They have profoundly impaired psychomotor development and may die in infancy or early childhood. Those that survive are unable to sit or walk. Sural nerve biopsy shows hypomyelination of the nerve fibers, and brain imaging often shows impaired myelination and cerebral and cerebellar atrophy. Nerve conduction velocities are severely decreased (about 10 m/s) or absent due to improper myelination (summary by Vallat et al., 2016 and Low et al., 2018). For a discussion of genetic heterogeneity of CHN, see CHN1 (605253).

Autosomal recessive progressive external ophthalmoplegia-6 (PEOB6) is characterized by ptosis and ophthalmoplegia as well as other clinical manifestations and multiple mtDNA deletions in muscle (Shintaku et al., 2022). For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (258450).