Hereditary Spastic Paraplegia with Mental Impairment, Thin Corpus Callosum and Amyotrophy: A Road Map to SPG11 Contributors.

Sir,

Hereditary spastic paraplegias are a genetically diverse group of disorders manifested clinically by lower limb weakness and spasticity. Harding[1] first classified HSP into pure form with lower limb spasticity, occasional and posterior column involvement, and complicated form, where the lower limb spasticity is associated with other neurological signs like amyotrophy, seizures, dementia, ataxia, deafness, extrapyramidal features, skeletal deformities and peripheral neuropathy.[2] On the basis of inheritance, it is classified as autosomal dominant, autosomal recessive or X-linked. Till date, 72 spastic gait gene (SPG) loci have been identified and numbered in order of their discovery.[3] The most common mutation associated with thin corpus callosum is in SPG 11, a cause of complicated HSP. It is characterized by spastic paraparesis with cognitive decline starting in early years of life. We report a case of complicated HSP with thin corpus callosum due to mutation in SPG 11.[2]

A 23-year-old male born out of a non-consanguineous marriage, presented with a history of progressive difficulty in walking since 2 years of age with frequent falls and irritable behaviour since 5 years of age. He had delayed developmental milestones and poor scholastic performance. The general physical examination was normal. On central nervous system examination, the patient had impaired attention, execution and judgement with mini mental status score of 24/30 and frontal assessment battery score of 13/18. He had spastic speech with elicitible jaw jerk. Bilateral optic atrophy was found on fundus examination. In addition, distal amyotrophy, bilateral pes cavus, hammer toes and spasticity present in lower limbs. Lower limb spasticity was present. Power was Medical Research Council (MRC) grade 4/5 in all groups of muscles. Deep tendon reflexes were brisk and bilateral Babinski's sign present. Sensory and cerebellar examination was unremarkable. His gait was spastic. Routine blood investigations, including liver function tests, renal profile, thyroid function tests and vitamin B12 levels were normal. Nerve conduction study and electromyography were normal. MRI of the brain revealed thin corpus callosum, generalized cortical atrophy [Figure 1] and bilateral symmetrical periventricular flaring [Figure 2] called 'ears of the lynx' sign. Thoracic spinal MRI showed thinning of the thoracic spinal cord with volume loss, but no obvious signal abnormalities [Figure 3]. Targeted gene sequencing was done showing a homozygous 2 base pair deletion in exon 36 of the SPG11 gene (chr15:;g. 44859720delAT; Depth 73x) that results in a frameshift and premature truncation of the protein 27 amino acids downstream to codon 2220 (p. Met2220AspfsTer27; ENST00000261866.7). It was consistent with the diagnosis of autosomal recessive HSP with a thin corpus callosum. Family screening and genetic counseling were advised. This variation has previously been reported in a homozygous state in a patient affected with hereditary spastic paraplegia.[2]

Figure 1

MRI brain T2W sagittal section showing thinning of corpus callosum with generalized cortical and cerebellar atrophy

Figure 2

MRI brain FLAIR axial section showing ears of the lynx sign

Figure 3

MRI spine T2W sagittal section showing dorsal cord thinning

The SPG 11 gene encodes the protein spatacsin,[4] the exact function of which is unknown. The genetic locus for SPG 11 is 15q21.1. There is a retrograde degeneration of the longest nerve fibres in the corticospinal tracts and posterior columns. Lesions in SPG11 have a broader spectrum involving TCC, ear of the lynx sign, amyotrophy, cerebellar ataxia and cognitive decline. TCC is one of the commonest indicators of SPG 11. However, TCC is a nonspecific finding associated with SPG1, SPG11, SPG15, SPG21, and SPG32 mutations.[5] The presence of additional signs such as cognitive decline, amyotrophy and white matter lesions increases the chance of identifying SPG11 mutations.[6] In our case, the presence of all these signs led to the early genetic testing particularly for SPG11 mutations and clinching the clinical diagnosis in a cost effective manner. Here, we highlight the constellation of findings including clinical features of spastic paraparesis, mental retardation, amyotrophy, and MRI finding of TCC, which should prompt a targeted genetic testing for SPG11mutations.

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