Pantothenate kinase-associated neurodegeneration (PKAN) is a type of neurodegeneration with brain iron accumulation (NBIA). The phenotypic spectrum of PKAN includes classic PKAN and atypical PKAN. Classic PKAN is characterized by early-childhood onset of progressive dystonia, dysarthria, rigidity, and choreoathetosis. Pigmentary retinal degeneration is common. Atypical PKAN is characterized by later onset (age >10 years), prominent speech defects, psychiatric disturbances, and more gradual progression of disease.

Hypohidrotic ectodermal dysplasia (HED) is characterized by hypotrichosis (sparseness of scalp and body hair), hypohidrosis (reduced ability to sweat), and hypodontia (congenital absence of teeth). The cardinal features of classic HED become obvious during childhood. The scalp hair is thin, lightly pigmented, and slow growing. Sweating, although present, is greatly deficient, leading to episodes of hyperthermia until the affected individual or family acquires experience with environmental modifications to control temperature. Only a few abnormally formed teeth erupt, at a later-than-average age. Physical growth and psychomotor development are otherwise within normal limits. Mild HED is characterized by mild manifestations of any or all the characteristic features.

Any centronuclear myopathy in which the cause of the disease is a mutation in the BIN1 gene.

Torsion dystonia-6 (DYT6) is an autosomal dominant movement disorder characterized by early involvement of craniofacial muscles with secondary generalization often involving the arms, and laryngeal dystonia that causes speech difficulties (review by Djarmati et al., 2009). Blanchard et al. (2011) provided a review of dystonia-6 and the THAP1 gene.

Progressive external ophthalmoplegia is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles and exercise intolerance. Patients with C10ORF2-linked adPEO may have other clinical features including proximal muscle weakness, ataxia, peripheral neuropathy, cardiomyopathy, cataracts, depression, and endocrine abnormalities (summary by Fratter et al., 2010). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant progressive external ophthalmoplegia, see PEOA1 (157640). PEO caused by mutations in the POLG gene (174763) is associated with more complicated phenotypes than PEO caused by mutations in the SLC25A4 (103220) or C10ORF2 genes (Lamantea et al., 2002).

Spinocerebellar ataxia type 20 (SCA20) is characterized by a slowly progressive ataxia and dysarthria. Approximately two thirds of those affected also display palatal tremor ("myoclonus") and/or abnormal phonation clinically resembling spasmodic adductor dysphonia. Dysarthria, which may be abrupt in onset, precedes the onset of ataxia in about two thirds of affected individuals, sometimes by a number of years. Hypermetric horizontal saccades (without nystagmus or disturbance of vestibulo-ocular reflex gain) are seen in about half of affected persons. Although minor pyramidal signs (brisk knee jerks, crossed adductor spread) may be seen, spasticity and extensor plantar responses are not. Cognition is normal. Clinical information is based on the findings in 16 personally examined affected members of a single Australian family of Anglo-Celtic descent.

X-linked spinocerebellar ataxia-6 with or without sideroblastic anemia (SCAX6) is an X-linked recessive disorder characterized by delayed motor development apparent in infancy with delayed walking (often by several years) due to ataxia and poor coordination. Additional features may include dysmetria, dysarthria, spasticity of the lower limbs, hyperreflexia, dysdiadochokinesis, strabismus, and nystagmus. The disorder is slowly progressive, and patients often lose ambulation. Brain imaging usually shows cerebellar atrophy. Most affected individuals have mild hypochromic, microcytic sideroblastic anemia, which may be asymptomatic. Laboratory studies show increased free erythrocyte protoporphyrin (FEP) and ringed sideroblasts on bone marrow biopsy. Female carriers do not have neurologic abnormalities, but may have subtle findings on peripheral blood smear (Pagon et al., 1985; D'Hooghe et al., 2012). For a discussion of genetic heterogeneity of X-linked spinocerebellar ataxia (SCAX), see SCAX1 (302500).

Dystonia-4 (DYT4), also known as whispering dysphonia, is an autosomal dominant neurologic disorder characterized by onset in the second to third decade of progressive laryngeal dysphonia followed by the involvement of other muscles, such as the neck or limbs. Some patients develop an ataxic gait (summary by Hersheson et al., 2013).

Neuroferritinopathy is an adult-onset progressive movement disorder characterized by chorea or dystonia and speech and swallowing deficits. The movement disorder typically affects one or two limbs and progresses to become more generalized within 20 years of disease onset. When present, asymmetry in the movement abnormalities remains throughout the course of the disorder. Most individuals develop a characteristic orofacial action-specific dystonia related to speech that leads to dysarthrophonia. Frontalis overactivity and orolingual dyskinesia are common. Cognitive deficits and behavioral issues become major problems with time.

The Russe type of hereditary motor and sensory neuropathy (HMSNR) is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy (summary by Sevilla et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth disease, see CMT4A (214400).

Idiopathic torsion dystonia (ITD) is a clinically and genetically heterogeneous group of movement disorders characterized by sustained dystonic muscle contractions causing involuntary twisting movements and/or postures, where causes such as cerebral lesions (especially of the basal ganglia), drugs, or other neurologic disorders have not been found. Adult-onset torsion dystonia usually remains focal and is localized in the upper part of the body (summary by Leube et al., 1996).

Autosomal dominant myopathy with rimmed ubiquitin-positive autophagic vacuolation (MRUPAV) is characterized by adult onset of slowly progressive skeletal muscle weakness variably affecting the distal or proximal lower limbs. Some patients may also have upper limb involvement or neck muscle weakness, but respiratory and bulbar involvement only rarely occurs. EMG studies show a myopathic process, and myotonia may also be observed. Skeletal muscle biopsy shows myopathic features, rimmed vacuoles, and abnormal subsarcolemmal protein aggregation with activation of the autophagy pathway (Ruggieri et al., 2020).

Primary dystonia, DYT17 type is a rare, genetic, isolated dystonia initially presenting as torticollis, and later progressing to segmental or generalized dystonia. Dysphonia and dysarthria also occur later in the disease course.

Dystonia 16 is one of many forms of dystonia, which is a group of conditions characterized by involuntary movements, twisting (torsion) and tensing of various muscles, and unusual positioning of affected body parts. Dystonia 16 can appear at any age from infancy through adulthood, although it most often begins in childhood.\n\nThe signs and symptoms of dystonia 16 vary among people with the condition. In many affected individuals, the disorder first affects muscles in one or both arms or legs. Tensing (contraction) of the muscles often sets the affected limb in an abnormal position, which may be painful and can lead to difficulty performing tasks, such as walking. In others, muscles in the neck are affected first, causing the head to be pulled backward and positioned with the chin in the air (retrocollis).\n\nIn dystonia 16, muscles of the jaw, lips, and tongue are also commonly affected (oromandibular dystonia), causing difficulty opening and closing the mouth and problems with swallowing and speech. Speech can also be affected by involuntary tensing of the muscles that control the vocal cords (laryngeal dystonia), resulting in a quiet, breathy voice or an inability to speak clearly. Dystonia 16 gradually gets worse, eventually involving muscles in most parts of the body.\n\nSome people with dystonia 16 develop a pattern of movement abnormalities known as parkinsonism. These abnormalities include unusually slow movement (bradykinesia), muscle rigidity, tremors, and an inability to hold the body upright and balanced (postural instability). In dystonia 16, parkinsonism is relatively mild if it develops at all.\n\nThe signs and symptoms of dystonia 16 usually do not get better when treated with drugs that are typically used for movement disorders.

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.

Thiamine metabolism dysfunction syndrome-5 (THMD5) is an autosomal recessive metabolic disorder due to an inborn error of thiamine metabolism. The phenotype is highly variable, but in general, affected individuals have onset in early childhood of acute encephalopathic episodes associated with increased serum and CSF lactate. These episodes result in progressive neurologic dysfunction manifest as gait disturbances, ataxia, dystonia, and spasticity, which in some cases may result in loss of ability to walk. Cognitive function is usually preserved, although mildly delayed development has been reported. These episodes are usually associated with infection and metabolic decompensation. Some patients may have recovery of some neurologic deficits (Mayr et al., 2011). For a discussion of genetic heterogeneity of disorders due to thiamine metabolism dysfunction, see THMD1 (249270).

A rare genetic isolated dystonia with characteristics of adult-onset non-progressive focal cervical dystonia typically manifesting with torticollis and occasionally accompanied by mild head tremor and essential-type limb tremor.

Mitochondrial DNA depletion syndrome-11 is an autosomal recessive mitochondrial disorder characterized by onset in childhood or adulthood of progressive external ophthalmoplegia (PEO), muscle weakness and atrophy, exercise intolerance, and respiratory insufficiency due to muscle weakness. More variable features include spinal deformity, emaciation, and cardiac abnormalities. Skeletal muscle biopsies show deletion and depletion of mitochondrial DNA (mtDNA) with variable defects in respiratory chain enzyme activities (summary by Kornblum et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).

Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset, even in adulthood. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain. Most patients also have cognitive impairment and axonal neuropathy and become severely disabled later in life (summary by Ghezzi et al., 2011). The disorder may present clinically as spinocerebellar ataxia or Leigh syndrome, or with psychiatric disturbances (Morino et al., 2014; Atwal, 2014; Nogueira et al., 2013). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).

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+").

Autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-2 (PEOB2) is a mitochondrial disorder characterized by adult onset of progressive external ophthalmoplegia, exercise intolerance, muscle weakness, and signs and symptoms of spinocerebellar ataxia, such as impaired gait and dysarthria. Some patients may have respiratory insufficiency. Laboratory studies are consistent with a defect in mtDNA replication (summary by Reyes et al., 2015). For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (258450).

Myoclonic dystonia-26 (DYT26) is an autosomal dominant neurologic disorder characterized by onset of myoclonic jerks affecting the upper limbs in the first or second decade of life. The disorder is progressive, and patients later develop dystonia with predominant involvement of the craniocervical regions and sometimes the trunk and/or lower limbs. Dystonia dominates the clinical picture (summary by Mencacci et al., 2015).

DYT-GNAL caused by a heterozygous GNAL pathogenic variant has been reported in more than 60 individuals to date. It is characterized by adult-onset isolated dystonia (i.e., no neurologic abnormalities other than tremor are evident on neurologic examination). The dystonia is most commonly focal and segmental, and rarely generalized. Dystonia is typically cervical in onset and commonly progresses to the cranial region (oromandibular/jaw, larynx, eyelids) and/or to one arm. Tremor reported in DYT-GNAL may be dystonic (i.e., occurring in a body part that shows at least minimal signs of dystonia) and may precede or follow the onset of dystonia. Intra- and interfamilial variability is considerable. DYT-GNAL caused by biallelic GNAL pathogenic variants, reported to date in two sibs from a consanguineous family, is characterized by mild intellectual disability and childhood-onset hypertonia that progresses to generalized dystonia.

KMT2B-related dystonia (DYT-KMT2B) is a complex childhood-onset (mean age 7 years) movement disorder described to date in 39 individuals. It is characterized by a progressive disease course evolving commonly from lower-limb focal dystonia into generalized dystonia with prominent cervical, cranial, and laryngeal involvement. Communication difficulties, secondary to articulation difficulties and low speech volume, are common. Bulbar dysfunction leads to impaired swallowing. Intellectual disability (ID) / developmental delay (DD) are commonly reported. Additional findings can include eye movement abnormalities, skin changes, psychiatric comorbidities (attention-deficit/hyperactivity disorder, anxiety, depression, and obsessive-compulsive disorder), myoclonus, seizures, spasticity, and sensorineural hearing loss. Many affected individuals follow a similar disease course, though milder and atypical findings have been described.

Congenital myasthenic syndrome-20 is an autosomal recessive neuromuscular disorder characterized by severe hypotonia associated with episodic apnea soon after birth. Patients have muscle weakness resulting in delayed walking, ptosis, poor sucking and swallowing, and generalized limb fatigability and weakness. EMG studies usually show a decremental response to repetitive nerve stimulation, and some patients may show a good response to AChE inhibitors (summary by Bauche et al., 2016). For a discussion of genetic heterogeneity of CMS, see CMS1A (601462).

Autosomal recessive progressive external ophthalmoplegia with mitochondrial DNA deletions-4 (PEOB4) is characterized by adult onset of eye muscle weakness and proximal limb muscle weakness associated with deletions of mtDNA on skeletal muscle biopsy, which results from defective mtDNA replication in post-mitotic muscle tissue. Additional features are more variable (summary by Ronchi et al., 2012). For a discussion of genetic heterogeneity of autosomal recessive PEO, see PEOB1 (258450).

Hereditary motor and sensory neuropathies (HMSN) are a heterogeneous group of peripheral nervous system disorders affecting motor and sensory function. HMSN I, also known as Charcot-Marie-Tooth (CMT) disease, or peroneal muscular atrophy, type 1, is a demyelinating neuropathy (see CMT1B; 118200) and HMSN II, also known as CMT type 2, is an axonal neuropathy (see CMT2A1; 118210). See also HMSN III (145900) and HMSN IV (266500). For an autosomal recessive disorder with similarities to HMSN V, see 607731.

HMNR5 is an autosomal recessive neurologic disorder characterized by young adult onset of slowly progressive distal muscle weakness and atrophy resulting in gait impairment and loss of reflexes due to impaired function of motor nerves. Sensation and cognition are not impaired (summary by Blumen et al., 2012). For a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320).

Oculopharyngodistal myopathy-1 (OPDM1) is an autosomal dominant disorder characterized by adult-onset ptosis, external ophthalmoplegia, facial muscle weakness, distal limb muscle weakness and atrophy, and pharyngeal involvement, resulting in dysphagia and dysarthria. Skeletal muscle biopsy shows myopathic changes with rimmed vacuoles. There are variable manifestations of the disorder regarding muscle involvement and severity (summary by Ishiura et al., 2019). Genetic Heterogeneity of Oculopharyngodistal Myopathy See also OPDM2 (618940), caused by trinucleotide repeat expansion in the GIPC1 gene (605072) on chromosome 19p13; OPDM3 (619473), caused by trinucleotide repeat expansion in the NOTCH2NLC gene (618025) on chromosome 1q21; and OPDM4 (619790), caused by trinucleotide repeat expansion in the RILPL1 gene (614092) on chromosome 12q24. Oculopharyngeal muscular dystrophy (OPMD; 164300) is a similar disorder with overlapping features. It is caused by a similar heterozygous trinucleotide repeat expansion in the PABPN1 gene (602279) (summary by Durmus et al., 2011).

Oculogastrointestinal neurodevelopmental syndrome (OGIN) is characterized by microphthalmia and/or coloboma in association with other congenital anomalies, including imperforate anus, horseshoe kidney, and structural cardiac defects. Hearing loss and severe developmental delay are also observed in most patients (Zha et al., 2020; Mor-Shaked et al., 2021).

Oculopharyngeal muscular dystrophy-2 (OPMD2) is an autosomal dominant muscle disorder characterized by early-onset ptosis, ophthalmoplegia, dysphagia, variable respiratory insufficiency, and proximal limb muscle weakness. Most patients have onset in the first years of life, although rare patients have onset in their teens. The disorder is slowly progressive and the severity is highly variable; the most severely affected individuals lose ambulation and may require tube-feeding or noninvasive ventilation (Kim et al., 2022). For a discussion of genetic heterogeneity of OPMD, see OPMD1 (164300).