Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders characterized by slowly progressive spastic pyramidal weakness of the lower extremity with or without additional neurological symptoms and signs. To date, more than 80 types have been described with different genetic loci based on genetic linkage analysis and identification of gene variants. Mutations of HSP‐related genes can be inherited in an autosomal recessive, autosomal dominant or X‐linked pattern with an age range between early childhood and 70 years. 1 Clinically, HSPs are classified into a pure form (lower limb spastic pyramidal weakness) and a complicated form (additional neurological signs such as cognitive impairment, seizures, muscle atrophy, and peripheral neuropathy). 2
Spastic paraplegia type 78 (SPG78) is an autosomal recessive disorder caused by mutations in the ATP13A2 gene (OMIM*610513) located on chromosome 1p36. 3 Affected individuals are usually adults who present with spastic pyramidal weakness of the lower extremities with gait difficulties and loss of ambulation in severe cases. In addition, some patients may have cerebellar signs, oculomotor disturbances, psychiatric symptoms, and cognitive impairment. The phenotype is highly variable, and neuroimaging usually demonstrates cerebellar atrophy. 4 In this article, we report a young man with a complicated form of HSP and a confirmed homozygous mutation in the ATP13A2 gene leading to the diagnosis of SPG78.
A 40‐year‐old male IV‐2 presented to the neurology clinic with a history of gradually progressive difficulty in walking and unsteadiness that started at the age of 16 years. At intial presentation, he was found to have spastic lower limb weakness, hyperreflexia, non‐sustained bilateral ankle clonus, and dysarthria. He progressed slowly and became wheelchair‐bound at the age of 40 with florid motor and cerebellar signs as well as cognitive decline. He was a product of a highly consanguineous family as detailed in the family pedigree shown in Figure 1. Proband IV‐2 had a positive family history as one of his sisters IV‐4 had a similar phenotype diagnosed at 28 years of age (Fig. 1). On examination, he was conscious, alert, and oriented. Neurological examination showed intellectual disability with severe impaired reading, writing, and executive functions. He had a spastic gait with an inability to perform a tandem gait. Upper extremity motor examination revealed mild bilateral upper limb spasticity with normal power. Lower extremity motor examination revealed spasticity and brisk reflexes with spontaneously upgoing toes bilaterally. Cerebellar examination showed dysdiadochokinesia, dysmetria, and gaze‐evoked nystagmus. The nerve conduction study revealed a length‐dependent axonal polyneuropathy. Brain magnetic resonance imaging performed at presentation to our hospital at the age of 40 years revealed diffuse cerebellar hemispheres and vermis atrophy (Fig. 2). Whole exome sequencing identified a homozygous variant c.364C>T p.(Gln122*) in the ATP13A2 gene, which leads to a premature stop codon and subsequent messenger RNA (mRNA) degradation (nonsense‐mediated decay) or truncation of the protein. Segregation analysis identified the same variant in two sisters (Fig. 3). Although the two sisters carry the same genetic mutation, one was clinically affected with the same phenotype and the other was healthy because she was still in the adolescence age and has not developed the symptoms and signs yet. The variant was previously reported in the literature by Estrada‐Cuzcano et al. 5 The patient was managed with symptomatic medications and was referred for physiotherapy and occupational therapy. He was seen at regular intervals every 6 months with slow, but progressive clinical deterioration.
FIG. 1.
Family pedigree demonstrating the details of the proband's family. The asterisk * sign represents the available sample for the study.
FIG. 2.
MRI of the brain showing diffuse cerebellar atrophy.
FIG. 3.
Representative chromograph of ATP13A2 sanger sequencing read of the available family members.
The ATP13A2 gene was initially implicated in Kufor‐Rakeb syndrome. Subsequently, mutations in this gene were reported in neuronal ceroid lipofuscinosis and amyotrophic lateral sclerosis. 6 The first description of a mutation in ATP13A2 causing SPG78 was published by Kara et al 7 who reported a 46‐year‐old man born to a consanguineous Pakistani family. He presented with spastic quadriparesis, cognitive decline, oculomotor abnormalities, and musculoskeletal deformities. Subsequently, van de Warrenburg et al 8 reported another case of a 37‐year‐old male with the typical presentation of the disease. A year later, Estrada‐Cuzcano et al 5 reported five patients from three unrelated families. The mean age at onset in these cases was 32 years, and all patients had the complex form of HSP. In addition, Erro et al 6 and Estiar et al 4 reported one and three additional patients with homozygous ATP13A2 mutations and typical phenotype, respectively. Furthermore, Odake et al 3 reported three siblings in one family with a complicated form of HSP accompanied by intellectual disability and psychiatric symptoms with a novel homozygous ATP13A2 mutation. The previously reported cases are summarized in Table 1.
TABLE 1.
Summary of clinical and paraclinical characteristics of patients with SPG78
| Study | Age at examination, y | Sex | Mutation | Important symptoms reported | Important observed signs | Neuroimaging | Nerve conduction study |
|---|---|---|---|---|---|---|---|
| Kara et al 7 | 18 | M | c.3017_3019del | Ataxia, falls, and cognitive decline | Spastic quadriplegia, bilateral pes cavus, and prominent eye signs (bilateral divergent squints and nystagmus on lateral gaze and reduced upgaze) | Cerebral atrophy and subtle abnormalities of the basal ganglia | Not available |
| van de Warrenburg et al 8 | 37 | M | c.2675G>A | Gait difficulty and cognitive decline | Spastic quadriplegia, weakness, positive Babinski sign, extra‐pyramidal signs, and upgaze limitation | Cerebral and cerebellar atrophy | Not available |
| Estrada‐Cuzcano et al 5 | 50 | M | c.1550C>T | Gait difficulty and verbal memory deficit | Spastic paraplegia, lower limb weakness, brisk reflexes all over, and positive Babinski sign | Cerebellar > cortical atrophy | Axonal motor and sensory polyneuropathy |
| 40 | M | c.1550C>T | Gait difficulty | Spastic paraplegia, lower limb weakness, brisk reflexes all over, and positive Babinski sign | Mild cortical atrophy periventricular white matter changes, “ear of lynx sign” | Normal | |
| 50 | M | c.1550C>T | Gait difficulty and verbal memory deficit | Spastic paraplegia, lower limb weakness, brisk reflexes all over, and positive Babinski sign | Cerebellar > cortical atrophy | Axonal motor and sensory polyneuropathy | |
| 47 | F | c.364C>T | Gait difficulty, severe dementia, and labile motivation | Spastic paraplegia, lower limb weakness, brisk reflexes in the lower limb, and vertical gaze palsy | Cerebellar > cortical mesencephalic atrophy, thin corpus callosum, Hydrocephalus, periventricular white matter changes | Mixed axonal demyelinating motor polyneuropathy | |
| 39 | F | c.364C>T | Gait difficulty, severe dementia, aggression, and hallucination | Spastic paraplegia, weakness all over, brisk reflexes all over, positive Babinski sign, extrapyramidal signs, and horizontal and vertical gaze palsy | Cerebellar > cortical atrophy, “ear of lynx sign” | Mild axonal sensory polyneuropathy | |
| Erro et al 6 | N/A | M | c.2629G>A | Gait difficulty and intellectual disability | Spastic quadriplegia, brisk reflexes all over, positive Babinski sign, and extrapyramidal signs | Generalized atrophy | Not available |
| Estiar et al 4 | 44 | F | c.insAAdelC | Gait difficulty, cognitive decline, aggressive behavior, excessive laughing, and seizures | Spastic paraplegia, lower limb weakness, brisk reflexes in the lower limb, positive Babinski sign, and extrapyramidal signs | Diffuse cerebellar atrophy | Not available |
| 31 | M | c.2126G>C | Gait difficulty, cognitive decline, delusions, and hallucinations | Spastic paraplegia, lower limb weakness, brisk reflexes all over, positive Babinski sign, and muscle atrophy | Diffuse cerebral and cerebellar atrophy, hypoplasia of the corpus callosum | Not available | |
| 32 | M | c.2158G>T | Gait difficulty, learning difficulty, psychotic episodes, and paranoid delusions | Spastic paraplegia, lower limb weakness, and positive Babinski sign | Cortical and cerebellar atrophy with signs of leukoencephalopathy in semioval centers, especially on the right side | Not available | |
| Odake et al 3 | 49 | F | c.[2654C>A] | Gait difficulty, intellectual disability, severe dementia, delusions, and seizures | Spastic paraplegia, weakness all over, brisk reflexes all over, muscle atrophy, positive Babinski sign, extrapyramidal signs, and supranuclear palsy | Diffuse cerebral and cerebellar atrophy, thin corpus callosum | Mild axonal motor and sensory polyneuropathy |
| 45 | F | c.[2654C>A] | Gait difficulty, intellectual disability, severe dementia, irritability, empty smile, and seizures | Spastic paraplegia, weakness all over, brisk reflexes all over, muscle atrophy, positive Babinski sign, extrapyramidal signs, and upgaze limitation | Diffuse cerebral and cerebellar atrophy, thin corpus callosum | Mild axonal motor and sensory polyneuropathy | |
| 42 | F | Not examined | Gait difficulty, intellectual disability, severe dementia, hallucinations, and delusions | Spastic paraplegia, weakness all over, brisk reflexes all over, muscle atrophy, and positive Babinski sign | Diffuse cerebral and cerebellar atrophy | Mild axonal motor and sensory polyneuropathy | |
| This report | 40 | M | c.364C>T | Gait difficulty and cognitive decline | Spastic paraplegia, weakness all over, brisk reflexes all over, positive Babinski sign, and gaze‐evoked nystagmus | Diffuse cerebellar hemispheres and vermis atrophy | Length‐dependent axonal polyneuropathy |
The ATP13A2 gene encodes a lysosomal enzyme, which serves as an inorganic cation transporter involved in the regulation of endolysosomal cargo sorting and neuronal integrity. In addition, it contributes to cellular zinc homeostasis and cellular protection against Mn (2+) and Zn (2+) toxicity and mitochondrial stress. These functions are dependent on the ability of the ATPase to undergo autophosphorylation. Mutations in the ATP13A2 gene result in loss of autophosphorylation and subsequent loss of function and disease occurrence. 5 , 9
On reviewing the literature, a total of 14 cases of SPG78 were previously reported. 3 , 4 , 5 , 6 , 7 , 8 , 10 They all share common symptoms and signs, including gait difficulty, cognitive decline, weakness, and hyperreflexia. Variable clinical features included seizures, extrapyramidal signs, and supranuclear palsy. Our patient had a typical SPG78 phenotype. Several clinical and paraclinical features were missed in this case by several hospitals before arrival at our center. These include slow‐onset disease that started in adolescence, progressive course, strong family history, involvement of two major pathways (cerebellum and corticospinal tract), and the neuroimaging finding of pan‐cerebellar atrophy. In addition, there was no etiological explanation for this disorder in this young man, including negative history of alcohol abuse, toxic/metabolic derangement, or space‐occupying lesion. Positive genetic testing in our patient was the reason for investigating other members of his family.
In conclusion, we report a rare case of adult‐onset SPG78 in a Saudi patient with a confirmed homozygous mutation in the ATP13A2 gene. Given the low prevalence of the disease as well as heterogeneity and variability of its presenting symptoms, SPG78 may be difficult to diagnose. However, early diagnosis is important to prevent unnecessary extensive investigations, facilitate early symptomatic management, and provide genetic counseling for family planning to those affected and their first and second‐degree relatives. To the best of our knowledge, this is the first case of SPG78 coming from the Arab world and the Middle East.
Author Roles
(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.
H.A.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B.
B.S.: 1A, 1B, 1C, 2A, 2B, 2C, 3A, 3B.
S.A.: 1C, 2B, 2C, 3A, 3B.
F.A.: 1C, 2B, 2C, 3A, 3B.
A.A.A.: 2A, 2B, 2C, 3B.
M.I.N.: 2A, 2B, 2C, 3B
Disclosures
Ethical Compliance Statement
This study was approved by the institutional review board (IRB) of King Abdullah International Medical Research Center (KAIMRC). Informed consent was obtained from the patient to publish this case report. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.
Funding Sources and Conflicts of Interest
This research work was funded by Institutional Fund Project (IFPRC‐013‐247‐2020). We gratefully acknowledge technical and financial support from the Ministry of Education and King Abdulaziz University, Jeddah Saudi Arabia. The authors declare that they have no conflicts of interest.
Financial Disclosures for Previous 12 Months
The authors declare that there are no additional disclosures to report.
No conflict of interest or financial disclosure to declare.
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