The distal hereditary motor neuropathies

Abstract

The distal hereditary motor neuropathies (dHMN) comprise a heterogeneous group of diseases that share the common feature of a length-dependent predominantly motor neuropathy. Many forms of dHMN have minor sensory abnormalities and/or a significant upper-motor-neuron component, and there is often an overlap with the axonal forms of Charcot-Marie-Tooth disease (CMT2) and with juvenile forms of amyotrophic lateral sclerosis and hereditary spastic paraplegia. Eleven causative genes and four loci have been identified with autosomal dominant, recessive and X-linked patterns of inheritance. Despite advances in the identification of novel gene mutations, 80% of patients with dHMN have a mutation in an as-yet undiscovered gene. The causative genes have implicated proteins with diverse functions such as protein misfolding (HSPB1, HSPB8, BSCL2), RNA metabolism (IGHMBP2, SETX, GARS), axonal transport (HSPB1, DYNC1H1, DCTN1) and cation-channel dysfunction (ATP7A and TRPV4) in motor-nerve disease. This review will summarise the clinical features of the different subtypes of dHMN to help focus genetic testing for the practising clinician. It will also review the neuroscience that underpins our current understanding of how these mutations lead to a motor-specific neuropathy and highlight potential therapeutic strategies. An understanding of the functional consequences of gene mutations will become increasingly important with the advent of next-generation sequencing and the need to determine the pathogenicity of large amounts of individual genetic data.

Exome sequencing reveals HINT1 mutations as a cause of distal hereditary motor neuropathy

“…[4][5][6] The distal hereditary motor neuropathies (dHMNs) are much rarer and present with a progressive distal motor weakness without sensory abnormalities. 7,8 The disease usually starts in the lower limbs. Unusual presentations include dHMN with onset in the upper limbs or with vocal cord or diaphragm paralysis.…”

“…There is clinical and genetic overlap with the axonal form of CMT (CMT2) and with some motor neuron disorders (MNDs). 7,9 The inheritance pattern of dHMN can also be autosomal dominant, autosomal recessive or X-linked. A significant proportion of dHMN patients will have a negative family history and can be classified as apparently sporadic cases.…”

Autosomal Recessive Peripheral Neuropathy With Neuromyotonia (Aran-Nm): Description of a Clinical Case Confirmed by a Mutation in the Hint1 Gene

“…distal hereditary motor neuropathy -dHMN или HMN), для которых характерны изолированное аксональ-ное повреждение двигательных волокон без чувстви-тельных нарушений, прогрессирующая дистальная мышечная слабость и атрофия, дегенеративные изме-нения нейронов передних рогов спинного мозга [7]. Клинические симптомы dHMN и ШМТ2 нередко пере-крываются и зависят от возраста пациента и стадии заболевания [8]. Молекулярно-генетические причины dHMN удается установить примерно в 20% случаев [8].…”

“…Клинические симптомы dHMN и ШМТ2 нередко пере-крываются и зависят от возраста пациента и стадии заболевания [8]. Молекулярно-генетические причины dHMN удается установить примерно в 20% случаев [8]. В этой ситуации интерес представляют описания мутаций в гене HINT1 на хромосоме 5q23, обусловлива-ющих развитие специфической формы dHMN/ШМТ2 -ШМТ с нейромиотонией, или аутосомно-рецессив-ной периферической нейропатии с нейромиотонией (ARAN-NM) [7,9,10].…”

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

“…Additional investigations including magnetic resonance imaging of brain and spinal cord, and metabolic and genetic studies may be undertaken. Diagnostic algorithms based on phenotype guide genetic testing in DSMA, although the yield currently remains low [55]. If neurophysiological studies reveal characteristic patterns associated with diseases in muscle, nerve, or neuromuscular junction then muscle or nerve biopsy and edrophonium test may be undertaken.…”