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Peripheral axonal degeneration

MedGen UID:
871339
Concept ID:
C4025830
Finding
HPO: HP:0000764

Definition

Progressive deterioration of peripheral axons. [from HPO]

Conditions with this feature

Charcot-Marie-Tooth disease X-linked dominant 1
MedGen UID:
98290
Concept ID:
C0393808
Disease or Syndrome
GJB1 disorders are typically characterized by peripheral motor and sensory neuropathy with or without fixed CNS abnormalities and/or acute, self-limited episodes of transient neurologic dysfunction (especially weakness and dysarthria). Peripheral neuropathy typically manifests in affected males between ages five and 25 years. Although both men and women are affected, manifestations tend to be less severe in women, some of whom may remain asymptomatic. Less commonly, initial manifestations in some affected individuals are stroke-like episodes (acute fulminant episodes of reversible CNS dysfunction).
Amyotrophic neuralgia
MedGen UID:
320318
Concept ID:
C1834304
Disease or Syndrome
Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant form of recurrent focal neuropathy characterized clinically by acute, recurrent episodes of brachial plexus neuropathy with muscle weakness and atrophy preceded by severe pain in the affected arm.
Charcot-Marie-Tooth disease, axonal, with vocal cord paresis, autosomal recessive
MedGen UID:
375113
Concept ID:
C1843183
Disease or Syndrome
Charcot-Marie-Tooth disease dominant intermediate B
MedGen UID:
338346
Concept ID:
C1847902
Disease or Syndrome
Charcot-Marie-Tooth disease is a clinically and genetically heterogeneous disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Classification CMT neuropathy is subdivided into CMT1 (see 118200) and CMT2 (see 118210) types on the basis of electrophysiologic and neuropathologic criteria. CMT1, or hereditary motor and sensory neuropathy type I (HMSN I), is a demyelinating neuropathy, whereas CMT2, or HMSN II, is an axonal neuropathy. Most patients with CMT are classified as having CMT1 or CMT2 by use of a cut-off value of 38 m/s for the motor median nerve conduction velocity (NCV). However, in some families with CMT, patients have motor median NCVs ranging from 25 to 45 m/s. Families of this type were reported by Salisachs (1974) and Davis et al. (1978). Davis et al. (1978) proposed that this form be designated 'intermediate' CMT. Claeys et al. (2009) stated that some CMT families may have an even broader range of NCV than 25 to 45 m/s, with the lowest levels around 25 and the highest levels within the normal range (50+ m/s). They also suggested that the term 'intermediate' should not be used to describe a single NCV value, but rather the CMT subtype at the level of the family (e.g., in families with a range or combinations of NCV values). Berciano et al. (2017) provided a detailed review of the different forms of intermediate CMT, noting that diagnoses may be controversial because of variable classification issues. The authors presented an algorithm for the interpretation of electrophysiologic studies in CMT, and suggested that nerve conduction studies should be conducted on the upper arm (axilla to elbow). They noted that distal axonal degeneration can result in secondary myelination defects, which may cause significantly decreased motor NCV and CMAP values that may be misinterpreted. Genetic Heterogeneity of Autosomal Dominant Intermediate CMT In addition to CMTDIB, which is caused by mutation in the DNM2 gene, other forms of dominant intermediate CMT include CMTDIA (620378), mapped to chromosome 10q24-q25; CMTDIC (608323), caused by mutation in the YARS gene (603623) on chromosome 1p35; CMTDID (607791), caused by mutation in the MPZ gene (159440) on chromosome 1q22; CMTDIE with focal segmental glomerulosclerosis (CMTDIE; 614455), caused by mutation in the INF2 gene (610982) on chromosome 14q32; CMTDIF (615185), caused by mutation in the GNB4 gene (610863) on chromosome 3q26; and CMTDIG (617882), caused by mutation in the NEFL gene (162280) on chromosome 8p21.
Autosomal recessive distal spinal muscular atrophy 1
MedGen UID:
388083
Concept ID:
C1858517
Disease or Syndrome
Autosomal recessive distal hereditary motor neuronopathy-1 (HMNR1) is characterized by distal and proximal muscle weakness and diaphragmatic palsy that leads to respiratory distress. Without intervention, most infants with the severe form of the disease die before 2 years of age. Affected individuals present in infancy with inspiratory stridor, weak cry, recurrent bronchopneumonia, and swallowing difficulties. The disorder is caused by distal and progressive motor neuronopathy resulting in muscle weakness (summary by Perego et al., 2020). Genetic Heterogeneity of Autosomal Recessive Distal Hereditary Motor Neuronopathy See also HMNR2 (605726), caused by mutation in the SIGMAR1 gene (601978); HMNR3 (607088) (encompassing Harding HMN types III and IV), which maps to chromosome 11q13; HMNR4 (611067), caused by mutation in the PLEKHG5 gene (611101); HMNR5 (614881), caused by mutation in the DNAJB2 gene (604139); HMNR6 (620011), caused by mutation in the REEP1 gene (609139); HMNR7 (619216), caused by mutation in the VWA1 gene (611901); HMNR8 (618912), caused by mutation in the SORD gene (182500); HMNR9 (620402), caused by mutation in the COQ7 gene (601683); and HMRN10 (620542), caused by mutation in the VRK1 gene (602168).
Congenital cataracts-facial dysmorphism-neuropathy syndrome
MedGen UID:
346973
Concept ID:
C1858726
Congenital Abnormality
CTDP1-related congenital cataracts, facial dysmorphism, and neuropathy (CTDP1-CCFDN) is characterized by abnormalities of the eye (bilateral congenital cataracts, microcornea, microphthalmia, micropupils), mildly dysmorphic facial features apparent in late childhood, and a hypo-/demyelinating, symmetric, distal peripheral neuropathy. The neuropathy is predominantly motor at the onset and results in delays in early motor development, progressing to severe disability by the third decade of life. Secondary foot deformities and scoliosis are common. Sensory neuropathy develops after age ten years. Most affected individuals have a mild nonprogressive intellectual deficit and cerebellar involvement including ataxia, nystagmus, intention tremor, and dysmetria. All have short stature and most have subnormal weight. Adults have hypogonadotropic hypogonadism. Parainfectious rhabdomyolysis (profound muscle weakness, myoglobinuria, and excessively elevated serum concentration of creatine kinase usually following a viral infection) is a potentially life-threatening complication. To date all affected individuals and carriers identified have been from the Romani population.
Charcot-Marie-Tooth disease type 4A
MedGen UID:
347821
Concept ID:
C1859198
Disease or Syndrome
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.
Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia
MedGen UID:
395301
Concept ID:
C1859598
Disease or Syndrome
Ataxia with oculomotor apraxia type 1 (AOA1) is characterized by childhood onset of slowly progressive cerebellar ataxia, followed by oculomotor apraxia and a severe primary motor peripheral axonal motor neuropathy. The first manifestation is progressive gait imbalance (mean age of onset: 4.3 years; range: 2-10 years), followed by dysarthria, then upper-limb dysmetria with mild intention tremor. Oculomotor apraxia, usually noticed a few years after the onset of ataxia, progresses to external ophthalmoplegia. All affected individuals have generalized areflexia followed by a peripheral neuropathy and quadriplegia with loss of ambulation about seven to ten years after onset. Hands and feet are short and atrophic. Chorea and upper-limb dystonia are common. Intellect remains normal in some individuals; in others, different degrees of cognitive impairment have been observed.
Amyotrophic lateral sclerosis type 4
MedGen UID:
355983
Concept ID:
C1865409
Disease or Syndrome
Juvenile amyotrophic lateral sclerosis-4 (ALS4) is an autosomal dominant disorder characterized by distal muscle weakness and atrophy, normal sensation, and pyramidal signs, with onset of symptoms before the age of 25 years, a slow rate of progression, and a normal life span (summary by Chen et al., 2004). For a phenotypic description and a discussion of genetic heterogeneity of amyotrophic lateral sclerosis, see ALS1 (105400).
Charcot-Marie-Tooth disease type 4C
MedGen UID:
356581
Concept ID:
C1866636
Disease or Syndrome
SH3TC2-related hereditary motor and sensory neuropathy (SH3TC2-HMSN) is a demyelinating neuropathy characterized by severe spine deformities (scoliosis or kyphoscoliosis) and foot deformities (pes cavus, pes planus, or pes valgus) that typically present in the first decade of life or early adolescence. Other findings can include cranial nerve involvement (most commonly tongue involvement, facial weakness/paralysis, hearing impairment, dysarthria) and respiratory problems.
Charcot-Marie-Tooth disease axonal type 2P
MedGen UID:
482427
Concept ID:
C3280797
Disease or Syndrome
A rare genetic axonal hereditary motor and sensory neuropathy disorder with characteristics of adulthood-onset of slowly progressive, occasionally asymmetrical, distal muscle weakness and atrophy (predominantly in the lower limbs), pan-modal sensory loss, muscle cramping in extremities and/or trunk, pes cavus and absent or reduced deep tendon reflexes. Gait anomalies and variable autonomic disturbances, such as erectile dysfunction and urinary urgency, may be associated. The disease can be caused by homozygous or heterozygous mutation in the LRSAM1 gene on chromosome 9q33.
Mitochondrial complex III deficiency nuclear type 2
MedGen UID:
767519
Concept ID:
C3554605
Disease or Syndrome
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).

Professional guidelines

PubMed

Fukami Y, Koike H, Katsuno M
Expert Rev Neurother 2022 Nov-Dec;22(11-12):941-952. Epub 2023 Jan 17 doi: 10.1080/14737175.2022.2166831. PMID: 36609209
McCray BA, Scherer SS
Neurotherapeutics 2021 Oct;18(4):2269-2285. Epub 2021 Oct 4 doi: 10.1007/s13311-021-01099-2. PMID: 34606075Free PMC Article
Kuwabara S
Drugs 2004;64(6):597-610. doi: 10.2165/00003495-200464060-00003. PMID: 15018590

Recent clinical studies

Etiology

Hakonen JE, Sorrentino V, Avagliano Trezza R, de Wissel MB, van den Berg M, Bleijlevens B, van Ruissen F, Distel B, Baas F, Zelcer N, Weterman MAJ
Hum Mol Genet 2017 Jun 1;26(11):2034-2041. doi: 10.1093/hmg/ddx089. PMID: 28335037
Strickland AV, Rebelo AP, Zhang F, Price J, Bolon B, Silva JP, Wen R, Züchner S
J Peripher Nerv Syst 2014 Jun;19(2):152-64. doi: 10.1111/jns5.12066. PMID: 24862862

Diagnosis

Schreiber S, Schreiber F, Peter A, Isler E, Dörner M, Heinze HJ, Petri S, Tempelmann C, Nestor PJ, Grimm A, Vielhaber S
Muscle Nerve 2020 Apr;61(4):521-526. Epub 2020 Jan 22 doi: 10.1002/mus.26800. PMID: 31899543

Therapy

Müller T, Hellwig R, Muhlack S
Clin Neuropharmacol 2011 May-Jun;34(3):101-3. doi: 10.1097/WNF.0b013e318219dad0. PMID: 21543973

Prognosis

Christen M, Oevermann A, Rupp S, Vaz FM, Wever EJM, Braus BK, Jagannathan V, Kehl A, Hytönen MK, Lohi H, Leeb T
Mol Genet Metab 2024 Mar;141(3):108149. Epub 2024 Jan 21 doi: 10.1016/j.ymgme.2024.108149. PMID: 38277988

Clinical prediction guides

Christen M, Oevermann A, Rupp S, Vaz FM, Wever EJM, Braus BK, Jagannathan V, Kehl A, Hytönen MK, Lohi H, Leeb T
Mol Genet Metab 2024 Mar;141(3):108149. Epub 2024 Jan 21 doi: 10.1016/j.ymgme.2024.108149. PMID: 38277988
Müller T, Hellwig R, Muhlack S
Clin Neuropharmacol 2011 May-Jun;34(3):101-3. doi: 10.1097/WNF.0b013e318219dad0. PMID: 21543973

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