GDAP1-related hereditary motor and sensory neuropathy (GDAP1-HMSN) is a peripheral neuropathy (also known as a subtype of Charcot-Marie-Tooth disease) that typically affects the lower extremities earlier and more severely than the upper extremities. As the neuropathy progresses, the distal upper extremities also become severely affected. Proximal muscles can also become weak. Age at onset ranges from infancy to early childhood. In most cases, disease progression causes disabilities within the first or second decade of life. At the end of the second decade, most individuals are wheelchair bound. Disease progression varies considerably even within the same family. The neuropathy can be either of the demyelinating type with reduced nerve conduction velocities or the axonal type with normal nerve conduction velocities. Vocal cord paresis is common. Intelligence is normal. Life expectancy is usually normal, but on occasion may be reduced because of secondary complications.

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+").

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.

Peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome is a rare, syndromic genetic deafness characterized by a combination of muscle weakness, chronic neuropathic and myopathic features, hoarseness and sensorineural hearing loss. A wide range of disease onset and severity has been reported even within the same family.

Optic atrophy-11 (OPA11) is an autosomal recessive disorder characterized by delayed psychomotor development, intellectual disability, ataxia, optic atrophy, and leukoencephalopathy on brain imaging. Laboratory studies are consistent with mitochondrial dysfunction (summary by Hartmann et al., 2016). For a discussion of genetic heterogeneity of optic atrophy, see OPA1 (165500).

Mitochondrial form of axonal Charcot-Marie-Tooth disease-1 (CMTMA1) is inherited only through the maternal line. The disorder is characterized by onset of distal muscle weakness and atrophy mainly affecting the lower limbs and resulting in difficulty walking in the second decade of life, although both earlier and later onset can occur. Upper limb involvement often develops with time, and affected individuals have weakness and atrophy of the intrinsic hand muscles. Other features may include distal sensory impairment, foot deformities, scoliosis, hypo- or hyperreflexia, spastic paraparesis, and neurogenic bladder. Electrophysiologic studies are compatible with an axonal sensorimotor peripheral neuropathy, and muscle and nerve biopsy show evidence of mitochondrial dysfunction with decreased activities of respiratory complexes, mtDNA deletions, and mitochondrial hyperplasia (summary by Fay et al., 2020).

Inclusion body myopathy and brain white matter abnormalities (IBMWMA) is an autosomal dominant adult-onset disorder characterized predominantly by proximal limb girdle muscle weakness affecting the lower and upper limbs and resulting in gait difficulties and scapular winging. Additional features may include dysarthria, dysphagia, low back pain, and hyporeflexia. EMG is consistent with a myopathic process, although neuropathic findings have also been shown. Muscle biopsy shows fiber type variation, internal nuclei, rimmed vacuoles, and cytoplasmic protein aggregates or inclusions. Serum creatine kinase is usually elevated. Cognitive impairment or frontotemporal dementia occurs in some patients. The disorder is slowly progressive; some patients become wheelchair-bound after many years. Rare patients with this mutation develop ALS; some have both myopathy and ALS. Brain imaging shows white matter abnormalities using diffusion tensor imaging. The disorder is classified as multisystem proteinopathy-6 (MSP6) due to the characteristic disease mechanism of protein misfolding and abnormal tissue deposition (summary by Leoni et al., 2021).

Childhood-onset biotin-responsive peripheral motor neuropathy (COMNB) is an autosomal recessive disorder characterized predominantly by the onset of distal muscle weakness and atrophy late in the first decade of life. The disorder predominantly affects the upper limbs and hands, resulting in difficulties with fine motor skills. Some patients may have lower limb involvement, resulting in gait difficulties. Electrophysiologic studies and muscle biopsy are consistent with chronic denervation with axonal and demyelinating features. Rare patients may have additional neurologic signs, including spasticity, ataxia, and cerebellar signs. Sensation is intact, and patients have normal cognitive development. Treatment with biotin, pantothenic acid, and lipoic acid may result in clinical improvement (Holling et al., 2022).

Autosomal recessive distal hereditary motor neuronopathy-6 (HMNR6) is a neuromuscular disorder characterized by onset of distal muscle weakness in early infancy. Affected individuals often present at birth with distal joint contractures or foot deformities and show delayed motor development, often with inability to walk or frequent falls. Hypo- or hyperreflexia may be observed; limb muscle atrophy may also be present. Patients often show respiratory distress or diaphragmatic palsy. Electrophysiologic studies are consistent with a peripheral motor neuropathy without sensory involvement (Maroofian et al., 2019). For a discussion of genetic heterogeneity of autosomal recessive distal HMN, see HMNR1 (604320).

Autosomal dominant distal hereditary motor neuronopathy-10 (HMND10) is a neurologic disorder of the peripheral nerves characterized clinically by length-dependent motor neuropathy primarily affecting the lower limbs. Affected individuals have onset of distal muscle weakness and atrophy in early childhood that results in walking difficulties and gait abnormalities. Some have pyramidal signs, including hyperreflexia, suggesting the involvement of upper motor neurons. Electrophysiologic studies are consistent with a neurogenic process. More variable features may include mild intellectual disability, minor gyration defects on brain imaging, foot deformities, and connective tissue defects (1 family) (Capuano et al., 2016; Iacomino et al., 2020). For a discussion of genetic heterogeneity of autosomal dominant distal HMN, see HMND1 (182960).

Juvenile amyotrophic lateral sclerosis-27 (ALS27) is an autosomal dominant disorder characterized by early childhood-onset lower extremity spasticity manifesting as toe walking and gait abnormalities, followed by progressive lower motor neuron-mediated weakness without sensory signs or symptoms (Mohassel et al., 2021). For a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).

Amyotrophic lateral sclerosis-28 (ALS28) is an autosomal dominant neurodegenerative disorder characterized by adult onset of slowly progressive limb muscle weakness and atrophy resulting in gait difficulties, loss of ambulation, and distal upper limb weakness. Facial involvement is rare, but some patients may have respiratory insufficiency. EMG and muscle biopsy show active and chronic denervation. Patient-derived motor neurons show accumulation of TDP43 (605078) and toxic intranuclear RNA accumulation (Kume et al., 2023). For discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).