Case Reports in Neurological Medicine
Volume 2019 (2019), Article ID 7615605, 5 pages
https://doi.org/10.1155/2019/7615605

Case Report

CAPN1 Variants as Cause of Hereditary Spastic Paraplegia Type 76

Jesus Eduardo Garcia-Berlanga,¹ Mariana Moscovich,² Isaac Jair Palacios,¹ Alejandro Banegas-Lagos,¹ Augusto Rojas-Martinez,¹ and Daniel Martinez-Ramirez¹

¹Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo Leon, Mexico
²Department of Neurology, Christian-Albrechts University, Kiel, Germany

Correspondence should be addressed to Daniel Martinez-Ramirez; daniel.martinez@medicos.tecsalud.mx

Received 3 May 2019; Accepted 23 May 2019; Published 1 July 2019

Academic Editor: Federico Micheli

Copyright © 2019 Jesus Eduardo Garcia-Berlanga et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract.

Background. Autosomal recessive hereditary spastic paraplegias (HSP) are a rare group of hereditary neurodegenerative disorders characterized by spasticity with or without other symptoms. SPG11 gene is the most common cause of autosomal recessive HSP. We report a case of autosomal recessive spastic paraplegia type 76 due to heterozygous variants of CAPN1 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 in CAPN1. Conclusions. Clinicians should screen for CAPN1 mutation in a young female patient without significant family history with a spastic paraplegia syndrome associated with other symptoms.

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 in SPAST gene accounts for 40% of the autosomal dominant HSP. In the recessive HSP, the most frequent mutation is in SPG11. We report a case of autosomal recessive spastic paraplegia type 76 (SPG76, OMIM #616907) due to heterozygous variants of CAPN1 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 (Video 1), 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 in CAPN1 (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 of CAPN1 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>A
p.Trp392∗
Stop gain mutation
Homozygous
+
NA
NA

2
Latin American
NA
NA
NA
+
+
-
-
-
-
c.1176G>A
p.Trp392∗
NA
Homozygous
+
NA
NA

3
Latin American
NA
NA
NA
+
+
-
-
-
-
c.1176G>A
p.Trp392∗
NA
Homozygous
+
NA
NA

4
Latin American
22
37
F
+
+
-
-
-
-
c.1176G>A
p.Trp392∗
NA
Homozygous
-
NA
NA

5
Caucasian
20
46
F
+
+
+
-
-
-
c.675C>A
p.Tyr225∗
Novel LoF Mutation
Homozygous
-
NA
NA

6
Caucasian
35
51
M
+
+
+
-
-
-
c.675C>A
p.Tyr225∗
Novel LoF Mutation
Homozygous
-
NA
NA

7
Latin American
30
42
F
+
+
+
-
-
-
c.1176G>A
p.Trp392∗
c.618_619delAG
p.Gly208Glnfs∗7
LoF Mutation
Heterozygous
+
NA
NA

8
Latin American
38
-
M
+
+
+
-
-
-
c.1176G>A
p.Trp392∗
LoF Mutation
Homozygous
+
NA
NA

9
Arab
20
31
F
+
+
-
+
-
Ex:8
c.884G>C
p.Arg295Pro
LoF Mutation
Homozygous
+
NA
Normal

10
Arab
NA
NA
NA
NA
NA
NA
NA
NA
Ex:8
c.884G>C
p.Arg295Pro
LoF Mutation
Homozygous
+
NA
NA

11
Arab
NA
NA
NA
NA
NA
NA
NA
NA
Ex:8
c.884G>C
p.Arg295Pro
LoF Mutation
Homozygous
+
NA
NA

12
Arab
35
47
M
+
+
-
+
-
Ex:14
c.1579C>T
p.Gln527
Stop variant
Homozygous
+
NA
Moderate Sensory Axonal Neuropathy

13
Arab
36
44
F
+
+
+
+
-
Ex:14
c.1579C>T
p.Gln527
Stop variant
Homozygous
+
NA
Moderate Sensory Axonal Neuropathy

14
Arab
22
42
M
+
+
-
+
-
Ex:14
c.1579C>T
p.Gln527
Stop variant
Homozygous
+
Normal
NA

15
Arab
39
40
M
+
+
+
+
-
Ex:14
c.1579C>T
p.Gln527
Stop variant
Homozygous
+
NA
NA

16
Arab
NA
NA
NA
NA
NA
NA
NA
NA
Ex:14
c.1579C>T
p.Gln527
Stop variant
Homozygous
+
NA
NA

17
Arab
NA
NA
NA
NA
NA
NA
NA
NA
Ex:14
c.1579C>T
p.Gln527
Stop variant
Homozygous
+
NA
NA

18
Arab
NA
NA
NA
NA
NA
NA
NA
NA
Ex:14
c.1579C>T
p.Gln527
Stop variant
Homozygous
+
NA
NA

19
Caucasian
24
30
F
+
-
-
-
-
Ex:4
c.406delC
p.Pro136Argfs∗40
Deletion
Heterozygous
-
NA
Normal

20
Caucasian
33
35
M
+
-
-
-
-
Ex:4
c.406delC
p.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>A
P.Gly.332Arg
NA
Homozygous
+
Normal
Normal

28
Arab
30
54
F
+
+
+
+
-
Ex10
c. 1176G>A
p. Trp392
Nucleotide substitution
Heterozygous
+
Normal
Normal

29
Arab
15
30
F
+
+
+
+
-
Ex:10
c. 1176G>A
p. 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>T
p.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>A
c.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 of CAPN1-related SPG76 disorders. We recommend clinicians to consider screening for CAPN1 in a young female patient with spastic paraplegia with additional neurological symptoms without significant family history.

Abbreviations

HSP: | Hereditary spastic paraplegia
SPAST: | Spastin gene
SPG: | Spastic paraplegia gene
CAPN1: | Calpain 1 gene
MRI: | Magnetic resonance imaging.

Data Availability

All data generated or analyzed during the case report are included in the published article.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images or videos.

Conflicts of Interest

The authors report no financial or nonfinancial conflicts of interest.

Authors’ Contributions

Daniel Martinez-Ramirez and Jesus Eduardo Garcia-Berlanga were responsible for conception, organization, and execution. All the authors were responsible for the preparation of the manuscript: writing of the first draft, review and critique, and reading and approving the final version of the manuscript.

Acknowledgments

We would like to thank the patient for authorizing us to use her clinical data to make it available for the medical community.

Supplementary Materials

Video Legends: We can observe interrupted slow horizontal and vertical eye movements with slow horizontal saccades. She had spasticity and hyperreflexia more pronounced in lower extremities. She also showed bilateral Hoffman and Trömner signs, with clonus in lower extremities, and presence of Babinski sign bilaterally. She presented cervical dystonia with laterocollis to the left, and mild bradykinesia was observed during rapid movements. Finger to nose test showed dyssynergia and hypometric movements, rapid alternating movements with dysdiadochokinesia, past pointing, and finger chasing with dyssynergia and dysmetria more pronounced on left upper extremity. Gait was spastic type with scissoring legs. (Supplementary Materials)

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