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Motor axonal neuropathy

MedGen UID:
413108
Concept ID:
C2749625
Disease or Syndrome
Synonyms: Axonal motor neuropathy; Motor and axonal neuropathy
 
HPO: HP:0007002

Definition

Progressive impairment of function of motor axons with muscle weakness, atrophy, and cramps. The deficits are length-dependent, meaning that muscles innervated by the longest nerves are affected first, so that for instance the arms are affected at a later age than the onset of deficits involving the lower leg. [from HPO]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVMotor axonal neuropathy

Conditions with this feature

Glucocorticoid deficiency with achalasia
MedGen UID:
82889
Concept ID:
C0271742
Disease or Syndrome
Triple A syndrome is an inherited condition characterized by three specific features: achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus, the tube that carries food from the throat to the stomach. It can lead to severe feeding difficulties and low blood glucose (hypoglycemia). Addison disease, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of Addison disease include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of triple A syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two.\n\nMany of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. This part of the nervous system controls involuntary body processes such as digestion, blood pressure, and body temperature. People with triple A syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).\n\nPeople with this condition may have other neurological abnormalities, such as developmental delay, intellectual disability, speech problems (dysarthria), and a small head size (microcephaly). In addition, affected individuals commonly experience muscle weakness, movement problems, and nerve abnormalities in their extremities (peripheral neuropathy). Some develop optic atrophy, which is the degeneration (atrophy) of the nerves that carry information from the eyes to the brain. Many of the neurological symptoms of triple A syndrome worsen over time.\n\nPeople with triple A syndrome frequently develop a thickening of the outer layer of skin (hyperkeratosis) on the palms of their hands and the soles of their feet. Other skin abnormalities may also be present in people with this condition.\n\nAlacrima is usually the first noticeable sign of triple A syndrome, as it becomes apparent early in life that affected children produce little or no tears while crying. They develop Addison disease and achalasia during childhood or adolescence, and most of the neurologic features of triple A syndrome begin during adulthood. The signs and symptoms of this condition vary among affected individuals, even among members of the same family.
McLeod neuroacanthocytosis syndrome
MedGen UID:
140765
Concept ID:
C0398568
Disease or Syndrome
McLeod neuroacanthocytosis syndrome (designated as MLS throughout this review) is a multisystem disorder with central nervous system (CNS), neuromuscular, cardiovascular, and hematologic manifestations in males: CNS manifestations are a neurodegenerative basal ganglia disease including movement disorders, cognitive alterations, and psychiatric symptoms. Neuromuscular manifestations include a (mostly subclinical) sensorimotor axonopathy and muscle weakness or atrophy of different degrees. Cardiac manifestations include dilated cardiomyopathy, atrial fibrillation, and tachyarrhythmia. Hematologically, MLS is defined as a specific blood group phenotype (named after the first proband, Hugh McLeod) that results from absent expression of the Kx erythrocyte antigen and weakened expression of Kell blood group antigens. The hematologic manifestations are red blood cell acanthocytosis and compensated hemolysis. Alloantibodies in the Kell and Kx blood group system can cause strong reactions to transfusions of incompatible blood and severe anemia in affected male newborns of Kell-negative mothers. Females heterozygous for XK pathogenic variants have mosaicism for the Kell and Kx blood group antigens. Although they usually lack CNS and neuromuscular manifestations, some heterozygous females may develop clinical manifestations including chorea or late-onset cognitive decline.
Charcot-Marie-Tooth disease X-linked recessive 4
MedGen UID:
162891
Concept ID:
C0795910
Disease or Syndrome
X-linked recessive Charcot-Marie-Tooth disease-4 with or without cerebellar ataxia (CMTX4) is a mitochondrial disorder manifest as progressive neurologic dysfunction with highly variable features. The age at onset ranges from infancy to young adulthood, and patients can present with different features, including hearing loss, delayed motor development, or difficulty walking due to peripheral neuropathy and/or cerebellar ataxia. Most patients develop all features, including a progressive sensorimotor axonal neuropathy and deafness due to auditory neuropathy. Additional more variable features can include cognitive impairment, cerebellar atrophy on brain imaging, cerebellar signs, such as dysarthria, abnormal extraocular movements, tremor, and dysmetria, as well as spasticity. There is significant intrafamilial variability: the variable features are consistent with mitochondrial dysfunction. Prolonged treatment with riboflavin may result in some mild improvement in the ataxia (summary by Rinaldi et al., 2012, Heimer et al., 2018, Bogdanova-Mihaylova et al., 2019).
Spastic paraplegia, optic atropy, and neuropathy
MedGen UID:
324411
Concept ID:
C1836010
Disease or Syndrome
Spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is an autosomal recessive neurodegenerative disorder characterized by early-onset progressive spastic paraplegia resulting in loss of independent ambulation in the teenage years. Additional features include optic atrophy, later onset of sensorimotor peripheral neuropathy, and progressive joint contractures; cognition remains intact (summary by Melo et al., 2015).
Charcot-Marie-Tooth peroneal muscular atrophy, X-linked, with aplasia cutis congenita
MedGen UID:
337105
Concept ID:
C1844864
Disease or Syndrome
Giant axonal neuropathy 1
MedGen UID:
376775
Concept ID:
C1850386
Disease or Syndrome
GAN-related neurodegeneration comprises a phenotypic continuum ranging from severe (sometimes called classic giant axonal neuropathy) to milder pure early-onset peripheral motor and sensory neuropathies. The classic giant axonal neuropathy phenotype typically manifests as an infantile-onset neurodegenerative disorder, starting as a severe peripheral motor and sensory neuropathy and evolving into central nervous system impairment (intellectual disability, seizures, cerebellar signs, and pyramidal tract signs). Most affected individuals become wheelchair dependent in the second decade of life and eventually bedridden with severe polyneuropathy, ataxia, and dementia. Death usually occurs in the third decade. At the milder end of the spectrum are predominantly motor and sensory neuropathies (with little to no CNS involvement) that overlap with the axonal form of Charcot-Marie-Tooth neuropathies.
Hereditary spastic paraplegia 14
MedGen UID:
343157
Concept ID:
C1854568
Disease or Syndrome
A rare complex hereditary spastic paraplegia with characteristics of adulthood onset of slowly progressive spastic paraplegia of lower limbs presenting with spastic gait, hyperreflexia and mild lower limb hypertonicity associated with mild intellectual disability, visual agnosia, short and long-term memory deficiency and mild distal motor neuropathy. Bilateral pes cavus and extensor plantar responses are also associated.
Neurodegeneration with brain iron accumulation 4
MedGen UID:
482001
Concept ID:
C3280371
Disease or Syndrome
Mitochondrial membrane protein-associated neurodegeneration (MPAN) is characterized initially by gait changes followed by progressive spastic paresis, progressive dystonia (which may be limited to the hands and feet or more generalized), neuropsychiatric abnormalities (emotional lability, depression, anxiety, impulsivity, compulsions, hallucinations, perseveration, inattention, and hyperactivity), and cognitive decline. Additional early findings can include dysphagia, dysarthria, optic atrophy, axonal neuropathy, parkinsonism, and bowel/bladder incontinence. Survival is usually well into adulthood. End-stage disease is characterized by severe dementia, spasticity, dystonia, and parkinsonism.
Peroxisome biogenesis disorder 6B
MedGen UID:
766862
Concept ID:
C3553948
Disease or Syndrome
The overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD) represent the milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood. Some patients with PEX10 mutations have a milder disorder characterized by childhood-onset cerebellar ataxia and neuropathy without mental retardation (summary by Waterham and Ebberink, 2012). For a complete phenotypic description and a discussion of genetic heterogeneity of PBD(NALD/IRD), see 601539. Individuals with mutations in the PEX10 gene have cells of complementation group 7 (CG7, equivalent to CGB). For information on the history of PBD complementation groups, see 214100.
Neurodevelopmental disorder with hypotonia, neuropathy, and deafness
MedGen UID:
1382171
Concept ID:
C4479603
Disease or Syndrome
SPTBN4 disorder is typically characterized by severe-to-profound developmental delay and/or intellectual disability, although two individuals in one family had a milder phenotype, including one individual with normal cognitive development. Speech and language skills are often severely limited. Affected individuals rarely achieve head control. Most are unable to sit, stand, or walk. Affected individuals typically have congenital hypotonia that may transition to hypertonia. Axonal motor neuropathy leads to hyporeflexia/areflexia and weakness, which can result in respiratory difficulties requiring ventilatory support. Most affected individuals require tube feeding for nutrition. Half of affected individuals develop seizures. Cortical visual impairment and auditory neuropathy have also been reported.
Neurodegeneration with brain iron accumulation 6
MedGen UID:
1387791
Concept ID:
C4517377
Disease or Syndrome
Neurodegeneration with brain iron accumulation refers to a group of neurodegenerative disorders characterized by progressive motor and cognitive dysfunction beginning in childhood or young adulthood. Patients show extrapyramidal motor signs, such as spasticity, dystonia, and parkinsonism. Brain imaging shows iron accumulation in the basal ganglia (summary by Dusi et al., 2014). For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).
Neuronopathy, distal hereditary motor, type 9
MedGen UID:
1617571
Concept ID:
C4540265
Disease or Syndrome
HMND9 is an autosomal dominant neurologic disorder characterized by juvenile onset of slowly progressive distal muscle weakness and atrophy affecting both the lower and upper limbs (summary by Tsai et al., 2017). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant distal HMN, see HMND1 (182960).
Pontocerebellar hypoplasia, type 1D
MedGen UID:
1648387
Concept ID:
C4748058
Disease or Syndrome
Pontocerebellar hypoplasia type 1D (PCH1D) is a severe autosomal recessive neurologic disorder characterized by severe hypotonia and a motor neuronopathy apparent at birth or in infancy. Patients have respiratory insufficiency, feeding difficulties, and severely delayed or minimal gross motor development. Other features may include eye movement abnormalities, poor overall growth, contractures. Brain imaging shows progressive cerebellar atrophy with relative sparing of the brainstem (summary by Burns et al., 2018). For a general phenotypic description and a discussion of genetic heterogeneity of PCH, see PCH1A (607596).
Neurodegeneration, childhood-onset, with cerebellar atrophy
MedGen UID:
1648286
Concept ID:
C4748934
Disease or Syndrome
Childhood-onset neurodegeneration with cerebellar atrophy (CONDCA) is a severe autosomal recessive neurodevelopmental disorder affecting the central and peripheral nervous system. Patients present in the first year of life with global developmental delay, impaired intellectual development, poor or absent speech, and motor abnormalities. Brain imaging shows cerebellar atrophy. The severity is variable, but death in childhood may occur (Shashi et al., 2018).
Neuronopathy, distal hereditary motor, autosomal recessive 7
MedGen UID:
1786836
Concept ID:
C5543119
Disease or Syndrome
Autosomal recessive distal hereditary motor neuronopathy-7 (HMNR7) is characterized by onset of lower leg weakness in the first decade. Affected individuals have difficulty climbing stairs and problems standing on the heels. Some patients have later onset well into the adult years. Most patients have foot deformities, and some may have leg muscle atrophy. The disorder is slowly progressive and often involves the upper limbs. Muscle biopsy and electrophysiologic studies are consistent with both a myopathic process and an axonal motor neuropathy. Sensory abnormalities are not typically present, and patients remain ambulatory. The phenotype shows phenotypic overlap with distal hereditary motor neuropathy, but can distinguished by the presence of myopathic features (summary by Deschauer et al., 2021 and Pagnamenta et al., 2021). For a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320).
Charcot-Marie-Tooth disease, axonal, IIa 2II
MedGen UID:
1824000
Concept ID:
C5774227
Disease or Syndrome
Axonal Charcot-Marie-Tooth disease type 2II (CMT2II) is an autosomal dominant neurologic disorder characterized by a slowly progressive sensorimotor peripheral neuropathy affecting mainly the lower limbs, resulting in distal muscle weakness and atrophy and subsequent walking difficulties. Some patients may have upper limb involvement with atrophy of the intrinsic hand muscles. The age at onset is highly variable, ranging from infancy to adulthood. Electrophysiologic studies are usually consistent with an axonal process, although some may show intermediate or even demyelinating values (Park et al., 2020; Ando et al., 2022). One family with possible autosomal recessive inheritance has been reported (Bogdanova-Mihaylova et al., 2021). For a discussion of genetic heterogeneity of axonal CMT, see CMT2A1 (118210).
Spastic paraplegia 88, autosomal dominant
MedGen UID:
1824020
Concept ID:
C5774247
Disease or Syndrome
Autosomal dominant spastic paraplegia-88 (SPG88) is characterized by onset of symptoms in the first year of life. Affected individuals show delayed motor development with walking difficulties due to spasticity of the lower limbs. The disorder is slowly progressive, but variable in severity; some patients are unable to ambulate independently. Most patients have a pure form of the disorder, although rare patients have been reported to have additional features, including peripheral neuropathy, speech delay, ADHD, and nonspecific brain imaging abnormalities (Schob et al., 2021, Estiar et al., 2022, De Winter et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of autosomal dominant spastic paraplegia, see SPG3A (182600).
Neuronopathy, distal hereditary motor, autosomal dominant 11
MedGen UID:
1849676
Concept ID:
C5882697
Disease or Syndrome
Autosomal dominant distal hereditary motor neuronopathy-11 (HMND11) is a peripheral axonal motor neuropathy characterized by juvenile or young-adult onset of distal limb muscle weakness and atrophy mainly affecting the lower limbs, resulting in gait instability and walking difficulties. Foot deformities may also be present. The disorder is usually slowly progressive, and patients remain ambulatory until late adulthood. Some affected individuals may have distal upper limb and hand involvement or mild distal sensory abnormalities, but motor symptoms dominate the clinical picture. Electrophysiologic studies are consistent with a length-dependent axonal motor or sensorimotor neuropathy. Seizures are not present and brain imaging is normal (Beijer et al., 2019). One reported affected individual had a marfanoid habitus and mild speech delay with learning disabilities, suggesting possible expansion of the phenotypic spectrum (Ylikallio et al., 2020). For a discussion of genetic heterogeneity of autosomal dominant distal HMN, see HMND1 (182960).
Neuronopathy, distal hereditary motor, autosomal recessive 10
MedGen UID:
1846713
Concept ID:
C5882703
Disease or Syndrome
Autosomal recessive distal hereditary motor neuronopathy-10 (HMNR10) is a slowly progressive disorder characterized by distal muscle weakness and atrophy predominantly affecting the lower limbs and resulting in gait abnormalities; upper limb involvement often occurs. Most individuals have juvenile or adult onset, but some may show earlier onset in infancy or childhood. Although most affected individuals have a pure distal motor neuropathy, some may also have signs of upper motor neuron disease, including pyramidal signs and hyperreflexia, and some may show mild sensory involvement or mild respiratory insufficiency. Foot deformities and calf atrophy are commonly observed. Intellectual development, cognitive function, and brain imaging are typically normal. Electrophysiologic studies are consistent with an axonal motor (sometimes sensorimotor) neuropathy. In general, patients with earlier onset have a more severe disorder with faster progression (summary by El-Bazzal et al., 2019; Demaegd et al., 2022). El-Bazzal et al. (2019) and Lazo and Morejon-Garcia (2023) noted that VRK1-related motor neuron disease is clinically heterogeneous and has been described by various clinical terms, including spinal muscular atrophy, distal spinal muscular atrophy, amyotrophic lateral sclerosis (ALS), juvenile-onset ALS, hereditary motor and sensory neuropathy, Charcot-Marie-Tooth disease, and pure distal motor neuropathy. VRK1 mutations result in functional insufficiency. For a discussion of genetic heterogeneity of autosomal recessive HMN, see HMNR1 (604320).

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Adams D, Ando Y, Beirão JM, Coelho T, Gertz MA, Gillmore JD, Hawkins PN, Lousada I, Suhr OB, Merlini G
J Neurol 2021 Jun;268(6):2109-2122. Epub 2020 Jan 6 doi: 10.1007/s00415-019-09688-0. PMID: 31907599Free PMC Article
van Doorn PA
Presse Med 2013 Jun;42(6 Pt 2):e193-201. Epub 2013 Apr 28 doi: 10.1016/j.lpm.2013.02.328. PMID: 23628447
Kuwabara S
Drugs 2004;64(6):597-610. doi: 10.2165/00003495-200464060-00003. PMID: 15018590

Recent clinical studies

Therapy

Shang P, Zhu M, Wang Y, Zheng X, Wu X, Zhu J, Feng J, Zhang HL
J Neurol 2021 Jul;268(7):2402-2419. Epub 2020 Mar 5 doi: 10.1007/s00415-020-09742-2. PMID: 32140865
Esposito S, Longo MR
Autoimmun Rev 2017 Jan;16(1):96-101. Epub 2016 Sep 23 doi: 10.1016/j.autrev.2016.09.022. PMID: 27666816
Ansar V, Valadi N
Prim Care 2015 Jun;42(2):189-93. Epub 2015 Mar 20 doi: 10.1016/j.pop.2015.01.001. PMID: 25979580
Hughes RA, Cornblath DR
Lancet 2005 Nov 5;366(9497):1653-66. doi: 10.1016/S0140-6736(05)67665-9. PMID: 16271648
Kuwabara S
Drugs 2004;64(6):597-610. doi: 10.2165/00003495-200464060-00003. PMID: 15018590

Prognosis

Hamel JI, Logigian EL
Neurology 2023 May 16;100(20):e2134-e2140. Epub 2023 Mar 27 doi: 10.1212/WNL.0000000000207215. PMID: 36973043Free PMC Article
Restrepo-Jiménez P, Rodríguez Y, González P, Chang C, Gershwin ME, Anaya JM
Expert Opin Biol Ther 2018 Jun;18(6):619-631. Epub 2018 May 8 doi: 10.1080/14712598.2018.1468885. PMID: 29681203
van Doorn PA
Presse Med 2013 Jun;42(6 Pt 2):e193-201. Epub 2013 Apr 28 doi: 10.1016/j.lpm.2013.02.328. PMID: 23628447
Hughes RA, Cornblath DR
Lancet 2005 Nov 5;366(9497):1653-66. doi: 10.1016/S0140-6736(05)67665-9. PMID: 16271648
Kuwabara S
Drugs 2004;64(6):597-610. doi: 10.2165/00003495-200464060-00003. PMID: 15018590

Clinical prediction guides

Hamel JI, Logigian EL
Neurology 2023 May 16;100(20):e2134-e2140. Epub 2023 Mar 27 doi: 10.1212/WNL.0000000000207215. PMID: 36973043Free PMC Article
Zhang D, Geng H, Cao L, Li W
J Clin Neurophysiol 2022 May 1;39(4):317-323. Epub 2020 Nov 20 doi: 10.1097/WNP.0000000000000771. PMID: 32852287
Restrepo-Jiménez P, Rodríguez Y, González P, Chang C, Gershwin ME, Anaya JM
Expert Opin Biol Ther 2018 Jun;18(6):619-631. Epub 2018 May 8 doi: 10.1080/14712598.2018.1468885. PMID: 29681203
Bae JS, Yuki N, Kuwabara S, Kim JK, Vucic S, Lin CS, Kiernan MC
J Neurol Neurosurg Psychiatry 2014 Aug;85(8):907-13. Epub 2013 Dec 19 doi: 10.1136/jnnp-2013-306212. PMID: 24357682
van Doorn PA
Presse Med 2013 Jun;42(6 Pt 2):e193-201. Epub 2013 Apr 28 doi: 10.1016/j.lpm.2013.02.328. PMID: 23628447

Recent systematic reviews

Prado MB Jr, Adiao KJB, Turalde CWR, Dasig DA
Acta Neurol Belg 2024 Aug;124(4):1237-1250. Epub 2024 Mar 30 doi: 10.1007/s13760-024-02518-9. PMID: 38553651
Finsterer J
Int J Mol Sci 2022 Nov 17;23(22) doi: 10.3390/ijms232214222. PMID: 36430700Free PMC Article
Schulte EC, Hauer L, Kunz AB, Sellner J
Eur J Neurol 2021 Oct;28(10):3230-3244. Epub 2021 Jul 12 doi: 10.1111/ene.14952. PMID: 34060708Free PMC Article
Uncini A, Notturno F, Kuwabara S
J Neurol Neurosurg Psychiatry 2020 Mar;91(3):278-284. Epub 2020 Jan 14 doi: 10.1136/jnnp-2019-321890. PMID: 31937584
Liu J, Lian Z, Chen H, Shi Z, Feng H, Du Q, Zhang Q, Zhou H
J Neuroimmunol 2017 Dec 15;313:25-33. Epub 2017 Oct 7 doi: 10.1016/j.jneuroim.2017.10.003. PMID: 29153605

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