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Early-onset spastic paraplegia 4 due to a heterozygous contiguous deletion in a 3-year-old girl

 Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand, India

Date of Submission20-Apr-2021
Date of Decision11-Jan-2022
Date of Acceptance02-Mar-2022
Date of Web Publication30-Jan-2023

Correspondence Address:
Indar Kumar Sharawat,
Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpn.JPN_92_21


How to cite this URL:
Panda PK, Sharawat IK. Early-onset spastic paraplegia 4 due to a heterozygous contiguous deletion in a 3-year-old girl. J Pediatr Neurosci [Epub ahead of print] [cited 2023 Jun 3]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=368821

A 3-year-old girl with an uneventful perinatal period and normally attained motor, language, and social developmental milestones presented with bilateral toe walking, which was nonprogressive in nature for the past 1½ years. She did not have any other neurological or systemic complaints. Apart from brisk knee and ankle jerks and Babinski signs, the rest of the neurological examination in bilateral lower and upper limbs, including muscle bulk, power, tone, and sensations, was within normal limits. There was no diurnal fluctuation in the severity of toe walking, no difficulty in getting up from a sitting position, normal cognition and behavior. She was born to nonconsanguineous parents, and there was no family history of any neurological illness. A clinical possibility of metachromatic leukodystrophy and spastic paraparesis was considered.

Her magnetic resonance imaging (MRI) of the brain and spine, serum creatine phosphokinase levels, and nerve conduction study (NCS) were normal. Blood TMS, urine GCMS, blood ammonia, blood glucose, arterial lactate, serum vitamin B12 level, serum homocysteine level, blood lead level, serum biotinidase level, arul sulfatase A level, and plasma amino acid levels were within normal limits.

Whole-exome sequencing did not detect any pathogenic point mutation, but in silico CNV analysis showed a heterozygous contiguous deletion of size 106.91 kb spanning genomic location chr2:g.(32340771_32340904)_(2445282_32446593)del (CNV ratio: 0.53). The presence of this deletion was later confirmed by performing chromosomal microarray. This deletion encompassed the SPAST gene on chromosome 2, and contiguous gene deletions of this region have been previously shown to cause spastic paraplegia 4 (SPG4); according to ACMG classification, this CNV was classified as “likely pathogenic.” None of the parents was found to harbor this mutation, suggesting de novo origin. The parents were counseled about the nature and prognosis of the disease, and the child was advised to use ankle-foot orthosis, gait training, and regular follow-up.

Spastic paraplegia 4 (SPG4, also called SPAST-HSP) usually presents with insidiously progressive spasticity of bilateral lower limbs. More than half of the affected individuals show some weakness in the legs, impaired vibration sensation at the ankles, and disturbances with sphincter function, such as urinary urgency, incontinence, hesitancy, and increased frequency of micturition.[1] A few patients might show subtle cognitive impairment, pes cavus, and mild spastic dysarthria. Neuroimaging and nerve conduction studies are normal in most cases, whereas a few cases might show mild atrophy of the vermis, thinning of the corpus callosum, and/or subtle white matter changes in MRI brain and reduced CMAP amplitude and prolonged latency in NCS.[2] Females often show more diffuse and severe disease, with brisk upper limb reflexes. Those with late-onset disease surprisingly have a more rapid progression of the illness. Long-term follow-up studies over 20 years reveal that at least 50% of people require assistance in walking and 10% require a wheelchair. Classically most patients have symptom onset in young adulthood, although symptoms can start as late as 76 years and as young as one year of age.[3] In the most of the patients one parent is affected. Minority of the patients show de novo mutations but has considerable intrafamilial variations due to autosomal dominant inheritance pattern. This variation precludes the exact age of the onset of the symptoms, clinical course, and degree of neurodisability even if it is diagnosed by prenatal testing.[4] Thus, our case is atypical in presentation, as she had only toe walking as a symptom, onset from a very young age, and de novo mutation without any affected family member. Clinicians need to consider the possibility of hereditary spastic paraparesis (HSP) in cases with isolated toe walking, even late-onset HSP types such as SPG4, especially when it is accompanied by exaggerated deep tendon reflexes and Babinski signs, suggesting that an involvement of pyramidal tracts and neuroimaging of the brain and spine are normal. As SPG4 is sometimes caused by intragenic deletion of contiguous gene deletions, clinicians need to perform in chromosomal microarray apart from next-generation sequencing in such cases.[4],[5]

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   References Top

Rudenskaia GE, Sermiagina IG, Illarioshkin SN, Sidorova OP, Fedotov VP, Poliakov AV. [Hereditary spastic paraplegia type 4 (SPG4): clinical and molecular-genetic characteristics]. Zh Nevrol Psikhiatr Im S S Korsakova 2010;110:12-9.  Back to cited text no. 1
Solowska JM, Baas PW. Hereditary spastic paraplegia SPG4: what is known and not known about the disease. Brain 2015;138:2471-84.  Back to cited text no. 2
Rudenskaya GE, Kadnikova VA, Sidorova OP, Beetz C, Illarioshkin SN, Dadaly EL, et al. [Hereditary spastic paraplegia type 4 (SPG4) in russian patients]. Zh Nevrol Psikhiatr Im S S Korsakova 2019;119:11-20.  Back to cited text no. 3
Kadnikova VA, Rudenskaya GE, Stepanova AA, Sermyagina IG, Ryzhkova OP. Mutational spectrum of spast (spg4) and atl1 (spg3a) genes in Russian patients with hereditary spastic paraplegia. Sci Rep 2019;9: 14412.  Back to cited text no. 4
Fonknechten N, Mavel D, Byrne P, Davoine CS, Cruaud C, Bönsch D, et al. Spectrum of SPG4 mutations in autosomal dominant spastic paraplegia. Hum Mol Genet 2000;9:637-44.  Back to cited text no. 5


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