Posted - December 2016 in Research Highlights
Different types found
The two research studies reported here describe severe pain as a result of nerve damage associated with two different forms of HSP – SPG3A and SPG11.
SPG3A HSP and neuropathic pain syndrome
Profound pain, but only mild sensory neuropathy and foot ulcers should prompt the screening for SPG3A mutations.
Objective: To describe a family with a newly found ATL1 genetic variant and the associated phenotype.
Background: Mutations in the ATL1 gene are known to cause pure early onset autosomal dominant hereditary spastic paraplegia (SPG3A) and ulceromutilating sensory neuropathy, like HSN-1. We describe the detailed clinical and electrophysiological findings in the first family with ulceromutilating sensory neuropathy, along with spastic paraparesis, carrying the p.Ala354Pro likely pathogenic variant in ATL1.
Methods: Detailed clinical and electrophysiological studies were performed in affected and at risk family members. Motor and sensory conduction studies, were carried out on upper and lower limbs. Genetic analysis was carried out using a custom designed neurogenetic gene capture panel followed by massively parallel sequencing (MPS).
Results: Two affected family members were investigated, as well as one unaffected. Through the family history, 12 patients were found to have had the same phenotype, including three deceased family members. One affected family member was analysed by MPS, with the p.Ala354Pro likely pathogenic variant in ATL1 being the only significant finding. The second affected family member also carried the variant, while the unaffected family member did not.
The affected family members had characteristic history of a profound neuropathic pain syndrome, despite relative preservation of superficial sensory modalities. The patients also exhibited spastic paraparesis with hyper-reflexia. This resulted in recurrent painless foot ulcers and osteomyelitis. Nerve Conduction Studies (NCS) showed only a mild sensory neuropathy.
Conclusions: This novel ATL1 variant potentially expands the SPG3A phenotype. The combination of severe ulceromutilating neuropathy, a profound neuropathic pain syndrome, and only mild sensory neuropathy on NCS, along with spastic paraparesis, should prompt the screening for ATL1 mutations.
SOURCE: Neurology (2016) Volume: 86, Issue: 16 SUPPL. 1, Publisher: Lippincott Williams and Wilkins, Pages: no pagination ISBN: 0028-3878
Severe neuropathic pain syndrome, with ulceromutilating neuropathy and spastic paraparesis, associated with the P.ala354pro variant in atl1
Khade N., Ashton C., Davis M., Knezevic W.
SPG11 and severe neuropathy
The late manifestation of axonal peripheral nerve damage lead to severe axonal neuropathy and associated pain with SPG11.
Complex hereditary spastic paraplegia (HSP) is a clinically heterogeneous group of disorders usually inherited in an autosomal recessive manner. In the past, complex recessive spastic paraplegias have been frequently associated with SPG11 mutations but also with defects in SPG15, SPG7 and a handful of other rare genes. Pleiotropy exists in HSP genes, exemplified in the recent association of SPG11 mutations with CMT2.
In this study, we performed whole exome sequence analysis and identified two siblings with novel compound heterozygous frameshift SPG11 mutations. The mutations segregated with disease were not present in control databases and analysis of skin fibroblast derived mRNA indicated that the SPG11 truncated mRNA species were not degraded significantly by non-sense mediated mRNA decay.
These siblings had severe early-onset spastic paraplegia but later in their disease developed severe axonal neuropathy, neuropathic pain and blue/black foot discolouration likely caused by a combination of the severe neuropathy with autonomic dysfunction and peripheral oedema. We also identified a similar late-onset axonal neuropathy in a Cypriot SPG11 family.
Although neuropathy is occasionally present in SPG11, in our SPG11 patients reported here it was particularly severe, highlighting the association of axonal neuropathy with SPG11 and the late manifestation of axonal peripheral nerve damage.
SOURCE: J Neurol. 2016 Nov;263(11):2278-2286. Epub 2016 Aug 20. PMID: 27544499 PMCID: PMC5065903 DOI: 10.1007/s00415-016-8254-5
Severe axonal neuropathy is a late manifestation of SPG11.
Manole A1,2, Chelban V1,3, Haridy NA1, Hamed SA4, Berardo A5, Reilly MM1,2, Houlden H6,7.
1 Department of Molecular Neuroscience and Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
2 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
3 Department of Neurology, Medical University N. Testemitanu, Chisinau, Republic of Moldova.
4 Department of Neurology and Psychiatry, Faculty of Medicine, Assiut University Hospital, Assiut, Egypt.
5 Instituto de Neurociencias Conci Carpinella, Laboratorio de Neurobiologìa, Instituto de Investigaciónes Medicas “Mercedes y Martín Ferreyra”, INIMEC-CONICET-UNC, Córdoba, Argentina.
6 Department of Molecular Neuroscience and Neurogenetics Laboratory, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. [email protected]
7 MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK. [email protected]