Cargando…
Co-occurrence of CLCN2-related leukoencephalopathy and SPG56
FAMILY REPORT: Two rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and spastic paraplegia 56 (SPG56), were found in members of the same family. Two siblings presented with spastic paraplegia, cognitive impairment, bladder and bowel dysfunction and gait ataxia; their...
Autores principales: | , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984871/ https://www.ncbi.nlm.nih.gov/pubmed/36879630 http://dx.doi.org/10.1016/j.prdoa.2023.100189 |
_version_ | 1784900828171075584 |
---|---|
author | Almasoudi, Wejdan Nilsson, Christer Kjellström, Ulrika Sandeman, Kevin Puschmann, Andreas |
author_facet | Almasoudi, Wejdan Nilsson, Christer Kjellström, Ulrika Sandeman, Kevin Puschmann, Andreas |
author_sort | Almasoudi, Wejdan |
collection | PubMed |
description | FAMILY REPORT: Two rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and spastic paraplegia 56 (SPG56), were found in members of the same family. Two siblings presented with spastic paraplegia, cognitive impairment, bladder and bowel dysfunction and gait ataxia; their consanguineous parents were unaffected. Ophthalmological examination revealed chorioretinopathy. Brain MRI showed T2 hyperintensities and T1 hypointensities in the internal capsules, cerebral peduncles, pyramidal tracts and middle cerebellar peduncles. Both affected siblings were homozygous for CYP2U1 c.947A > T p.(Asp316Val), a known cause for SPG56. However, they were also homozygous for the novel variant CLCN2 c.607G > T, p.(Gly203Cys), classified as a variant of unknown significance. Testing of additional family members revealed homozygosity for both variants in an additional brother, whom we initially considered unaffected. Both male CLCN2 carriers were infertile, and review of the literature revealed one reported case with azoospermia, however the brother had no overt signs of SPG56. His testicular biopsy revealed incomplete maturation arrest in spermatogenesis; clinically we found mild memory impairment and hand tremor and MRI showed similar changes as his siblings. We consider CLCN2 c.607G > T pathogenic because of the neuroradiological and clinical findings, including azoospermia. CONCLUSION: Considerable workup may be required to determine the pathogenicity of novel variants, and to unambiguously associate phenotype with genotype. In very rare disorders, highly specific clinical or biomarker combinations provide sufficient evidence for a variant’s pathogenicity. Phenotypic variation of monogenic disorders described in the literature may be attributed to a second co-occurring monogenic disorder, especially in consanguineous families. SPG56 may have reduced penetrance. |
format | Online Article Text |
id | pubmed-9984871 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-99848712023-03-05 Co-occurrence of CLCN2-related leukoencephalopathy and SPG56 Almasoudi, Wejdan Nilsson, Christer Kjellström, Ulrika Sandeman, Kevin Puschmann, Andreas Clin Park Relat Disord Short Communications FAMILY REPORT: Two rare autosomal recessive neurological disorders, leukoencephalopathy with ataxia and spastic paraplegia 56 (SPG56), were found in members of the same family. Two siblings presented with spastic paraplegia, cognitive impairment, bladder and bowel dysfunction and gait ataxia; their consanguineous parents were unaffected. Ophthalmological examination revealed chorioretinopathy. Brain MRI showed T2 hyperintensities and T1 hypointensities in the internal capsules, cerebral peduncles, pyramidal tracts and middle cerebellar peduncles. Both affected siblings were homozygous for CYP2U1 c.947A > T p.(Asp316Val), a known cause for SPG56. However, they were also homozygous for the novel variant CLCN2 c.607G > T, p.(Gly203Cys), classified as a variant of unknown significance. Testing of additional family members revealed homozygosity for both variants in an additional brother, whom we initially considered unaffected. Both male CLCN2 carriers were infertile, and review of the literature revealed one reported case with azoospermia, however the brother had no overt signs of SPG56. His testicular biopsy revealed incomplete maturation arrest in spermatogenesis; clinically we found mild memory impairment and hand tremor and MRI showed similar changes as his siblings. We consider CLCN2 c.607G > T pathogenic because of the neuroradiological and clinical findings, including azoospermia. CONCLUSION: Considerable workup may be required to determine the pathogenicity of novel variants, and to unambiguously associate phenotype with genotype. In very rare disorders, highly specific clinical or biomarker combinations provide sufficient evidence for a variant’s pathogenicity. Phenotypic variation of monogenic disorders described in the literature may be attributed to a second co-occurring monogenic disorder, especially in consanguineous families. SPG56 may have reduced penetrance. Elsevier 2023-02-22 /pmc/articles/PMC9984871/ /pubmed/36879630 http://dx.doi.org/10.1016/j.prdoa.2023.100189 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Short Communications Almasoudi, Wejdan Nilsson, Christer Kjellström, Ulrika Sandeman, Kevin Puschmann, Andreas Co-occurrence of CLCN2-related leukoencephalopathy and SPG56 |
title | Co-occurrence of CLCN2-related leukoencephalopathy and SPG56 |
title_full | Co-occurrence of CLCN2-related leukoencephalopathy and SPG56 |
title_fullStr | Co-occurrence of CLCN2-related leukoencephalopathy and SPG56 |
title_full_unstemmed | Co-occurrence of CLCN2-related leukoencephalopathy and SPG56 |
title_short | Co-occurrence of CLCN2-related leukoencephalopathy and SPG56 |
title_sort | co-occurrence of clcn2-related leukoencephalopathy and spg56 |
topic | Short Communications |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9984871/ https://www.ncbi.nlm.nih.gov/pubmed/36879630 http://dx.doi.org/10.1016/j.prdoa.2023.100189 |
work_keys_str_mv | AT almasoudiwejdan cooccurrenceofclcn2relatedleukoencephalopathyandspg56 AT nilssonchrister cooccurrenceofclcn2relatedleukoencephalopathyandspg56 AT kjellstromulrika cooccurrenceofclcn2relatedleukoencephalopathyandspg56 AT sandemankevin cooccurrenceofclcn2relatedleukoencephalopathyandspg56 AT puschmannandreas cooccurrenceofclcn2relatedleukoencephalopathyandspg56 |