# CAPN1 Variants as Cause of Hereditary Spastic Paraplegia Type 76

Authors: Jesus Eduardo Garcia-Berlanga; Mariana Moscovich; Isaac Jair Palacios; Alejandro Banegas-Lagos; Augusto Rojas-Martinez; Daniel Martinez-Ramirez
Journal: Case Reports in Neurological Medicine
 (2019)

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## Abstract

Background. Autosomal recessive hereditary spastic paraplegias (HSP) are a rare group of hereditary neurodegenerative disorders characterized by spasticity with or without other symptoms.SPG11gene is the most common cause of autosomal recessive HSP. We report a case of autosomal recessive spastic paraplegia type 76 due to heterozygous variants ofCAPN1 in an Argentinean subject.Case Presentation. A 38-year-old Argentinean female presented with progressive gait problems and instability of 15-year duration. Oculomotor abnormalities, ataxia, bradykinesia, cervical dystonia, and lower limb pyramidal signs were observed. Brain MRI was unremarkable. Whole-exome sequencing analysis identified two heterozygous variants inCAPN1.Conclusions. Clinicians should screen forCAPN1 mutation in a young female patient without significant family history with a spastic paraplegia syndrome associated with other symptoms.


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## Body

## 1. Background

Hereditary spastic paraplegias (HSP) are a group of heterogeneous degenerative disorders characterized by lower limb spasticity and weakness due to progressive degeneration of corticospinal tracts [1]. HSP can present as a pure form only with pyramidal symptoms, or as a complex form associated with other symptoms. HSP are transmitted in all modes of inheritance [2]. The autosomal dominant mode of inheritance is the most prevalent representing 70% of cases. Mutation inSPAST gene accounts for 40% of the autosomal dominant HSP. In the recessive HSP, the most frequent mutation is inSPG11. We report a case of autosomal recessive spastic paraplegia type 76 (SPG76, OMIM #616907) due to heterozygous variants ofCAPN1 in an Argentinean subject.


## 2. Case Presentation

A 38-year-old Argentinean female presented with slowly progressive unsteadiness noticed first at age 23. She reported pronounced instability and gait problems as disease progressed. Her gait problems were described as short steps, with starting hesitation, fear of falling, and needing to hold from walls to avoid falling. She also reported several falls, dizziness, neck pain, and constipation. Symptoms progressed over the years affecting her mobility and functionality. She currently needs assistance for moving around. No relevant medical, family, or psychosocial history was reported. No past interventions were reported.On neurological examination (Video1), she presented dysarthria, interrupted slow horizontal and vertical eye movements, and slow horizontal saccades. She manifested spasticity and hyperreflexia more pronounced in her lower extremities. Mild cervical dystonia with bradykinesia was also observed. She showed ataxic symptoms more pronounced on her left upper extremity. Gait was spastic and no cognitive abnormalities were observed.Brain MRI with and without contrast was unremarkable. Due to the presence of a slowly progressive adult onset spastic-ataxia syndrome, associated with other neurological abnormalities, and facing the challenge of poor financial access, we decided to optimize our resources studying the patient using whole-exome sequencing (CentoDX™, Centogene AG, Germany). The analysis identified two variants inCAPN1 (MIM:114220) considered as probably pathogenic Class 2, according to the American College of Medical Genetics and Genomics criteria. She was heterozygous for a splicing mutation in intron 16 (c.1729+1G>A) and a second splicing mutation in intron 12 (c.1353+2T>C). Carrier testing in the parents was not performed. Due to the strong phenotypic overlap between the symptoms and previously reported cases, we consider the detected variants as pathogenic of SPG76.


## 3. Discussion

We report two pathogenic variants ofCAPN1 gene and the first case affecting two noncoding regions (introns) in a Latin-American patient. Table 1 describes all SPG76 reported cases in the literature [3, 4]. We observed that female patients are more commonly (67%) affected, with a mean age of onset of 19.8 years (Min. = 5, Max. = 39), most had family history of consanguinity (71%), and most were homozygous (77%). All initiated with lower limb spasticity, 85% reported upper limb spasticity, 58% showed ataxia, and 41% reported dysarthria. Our case also presented with oculomotor abnormalities. Three cases showed cerebellar atrophy and 1 spinal atrophy on MRI.Table 1
Clinical and genetical characteristics of SPG76 cases reported in the literature.
Ethnicity Age at onset Age at diagnosis Gender Lower limbs spasticity Upper limbs spasticity Ataxia Dysarthria Oculomotor Impairment Exon or Intron affected Mutation Type Heterozygous /Homozygous Consanguinity Brain MRI NCS and SSEP 1 Latin American NA NA NA + + - - - - c.1176G>Ap.Trp392∗ Stop gain mutation Homozygous + NA NA  2 Latin American NA NA NA + + - - - - c.1176G>Ap.Trp392∗ NA Homozygous + NA NA  3 Latin American NA NA NA + + - - - - c.1176G>Ap.Trp392∗ NA Homozygous + NA NA  4 Latin American 22 37 F + + - - - - c.1176G>Ap.Trp392∗ NA Homozygous - NA NA  5 Caucasian 20 46 F + + + - - - c.675C>Ap.Tyr225∗ Novel LoF Mutation Homozygous - NA NA  6 Caucasian 35 51 M + + + - - - c.675C>Ap.Tyr225∗ Novel LoF Mutation Homozygous - NA NA  7 Latin American 30 42 F + + + - - - c.1176G>Ap.Trp392∗c.618_619delAGp.Gly208Glnfs∗7 LoF Mutation Heterozygous + NA NA  8 Latin American 38 - M + + + - - - c.1176G>Ap.Trp392∗ LoF Mutation Homozygous + NA NA  9 Arab 20 31 F + + - + - Ex:8 c.884G>Cp.Arg295Pro LoF Mutation Homozygous + NA Normal  10 Arab NA NA NA NA NA NA NA NA Ex:8 c.884G>Cp.Arg295Pro LoF Mutation Homozygous + NA NA  11 Arab NA NA NA NA NA NA NA NA Ex:8 c.884G>Cp.Arg295Pro LoF Mutation Homozygous + NA NA  12 Arab 35 47 M + + - + - Ex:14 c.1579C>Tp.Gln527 Stop variant Homozygous + NA Moderate Sensory Axonal Neuropathy  13 Arab 36 44 F + + + + - Ex:14 c.1579C>Tp.Gln527 Stop variant Homozygous + NA Moderate Sensory Axonal Neuropathy  14 Arab 22 42 M + + - + - Ex:14 c.1579C>Tp.Gln527 Stop variant Homozygous + Normal NA  15 Arab 39 40 M + + + + - Ex:14 c.1579C>Tp.Gln527 Stop variant Homozygous + NA NA  16 Arab NA NA NA NA NA NA NA NA Ex:14 c.1579C>Tp.Gln527 Stop variant Homozygous + NA NA  17 Arab NA NA NA NA NA NA NA NA Ex:14 c.1579C>Tp.Gln527 Stop variant Homozygous + NA NA  18 Arab NA NA NA NA NA NA NA NA Ex:14 c.1579C>Tp.Gln527 Stop variant Homozygous + NA NA  19 Caucasian 24 30 F + - - - - Ex:4 c.406delCp.Pro136Argfs∗40 Deletion Heterozygous - NA Normal  20 Caucasian 33 35 M + - - - - Ex:4 c.406delCp.Pro136Argfs∗40 Deletion Heterozygous - Atrophy of spinal cord NA  21 Caucasian 19 22 F + + + - - Ex:4 c.1605+5G>A Mutation Splicing Heterozygous - Normal NA  22 Indian 33 43 F + + + + - Ex:3 c.337+1G>A Splice Mutation Homozygous + Mild cerebellar atrophy Normal  23 Indian NA NA F NA NA NA NA NA Ex:3 c.337+1G>A Splice Mutation Homozygous + NA NA  24 Caucasian 29 39 F + + + + + Ex:6 c.759+1G>A Donor splice site Homozygous + Mild cerebellar vermal atrophy NA  25 Caucasian 33 37 F + + + + - Ex:6 c.759+1G>A Donor splice site Homozygous + NA NA  26 Caucasian 5 16 M + - - - - - c.221GNA/p.(G74D)c.911CNT/p.(T304M)c.1418GNT/p.(R473L) missense Heterozygous - Normal Normal  27 Arab 21 37 F + + + + - - c.994G>AP.Gly.332Arg NA Homozygous + Normal Normal  28 Arab 30 54 F + + + + - Ex10 c. 1176G>Ap. Trp392 Nucleotide substitution Heterozygous + Normal Normal  29 Arab 15 30 F + + + + - Ex:10 c. 1176G>Ap. Trp392 Nucleotide substitution Heterozygous + Normal Normal  30 Asian 37 42 F + + + - - - c.2118+1G>T Donor Splice site Homozygous NA NA NA  31 Caucasian 23 23 M + - - - - - c.397C>T NA Homozygous + NA NA  32 Caucasian 20 20 F + - - - - - c.397C>T Mutation in DYSF Homozygous + NA NA  33 Asian 37 37 M + + + - - - c.843+1G>C Donor Splice Site Homozygous + NA NA  34 Caucasian 13 14 F + + + - - Ex: 13 c.1534C>Tp.Arg512Cys NA Homozygous - Small midbrain and ponds, cerebellar atrophy Delayed cortical wave defective conduction of large sensory fibers  35 (our case) Latin American 23 38 F + + + + + In: 12 and 16 c.1729+1G>Ac.1353+2T>C Donor Splice Mutation Heterozygous NA Normal NA Abbreviations. F: female, M: male, +: present, -: absent, LoF: loss of function, DYSF: dysferlin, MRI: magnetic resonance image, C: cerebral, S: spinal, NCS: nerve conduction studies, SSEP: somatosensory evoked potentials, NA: not available.In comparison with other published cases, we found similarities in that all of them presented lower limb spasticity and ataxia. The difference from our case was the oculomotor abnormalities, which was also reported in only one other case [5]. We suggest that the combined phenotype of spasticity and ataxia with oculomotor abnormalities, in a young female patient of Arab origin, could be a diagnostic clue for SPG76. The age of onset of our case was similar to that previously reported. All of the subjects experienced pronounced instability and gait problems as disease progresses [6].CAPN1 mutations account for 2.2% of autosomal recessive HSP.CAPN1 is located in chromosome 11q13 and encodes calpain 1, a calcium-activated cysteine protease that is widely present in the central nervous system. The exact role of calpain 1 in humans is unclear; however, studies in animal models suggest that calpain 1 is involved in synaptic plasticity, neuronal migration, neuronal necrosis, and maintenance [7].


## 4. Conclusions

Our report adds to the clinical and genetical spectrum ofCAPN1-related SPG76 disorders. We recommend clinicians to consider screening forCAPN1 in a young female patient with spastic paraplegia with additional neurological symptoms without significant family history.



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