Spastic Paraplegia Type 57: A Cerebral Palsy Mimic

Hereditary spastic paraplegias (HSP) are a heterogeneous group of gait disorders, which caused by a distal neuropathy of the longest corticospinal tract axons; ascending fibers are also often involved.[1] [2]

HSP can be associated with autosomal dominant or recessive inheritance patterns, and more than 67 HSP genes are currently known to date.[3]

Clinical features of HSP include weakness and spasticity of the lower extremities. HSP can be classified as pure (uncomplicated) or complex according to the absence or presence of additional neurological and non-neurological manifestations, including polyneuropathy, amyotrophy, optic and cerebellar atrophy, cognitive impairment, and epilepsy and neuroradiology findings such as thinning of the corpus callosum and skeletal abnormalities.[3]

Spastic paraplegia type 57 (SPG57) is an extremely rare cause of HSP. This condition has been associated with homozygous mutations of the TFG gene (3q12.2) encoding protein TFG, which is a highly conserved regulator of protein secretion and functions at the interface between the endoplasmic reticulum (ER) and ER-Golgi intermediate compartments. The transmission pattern of SPG57 is autosomal recessive.[4]

SPG57 is clinically characterized by profound lower limb spasticity (inability to walk independently), hyperreflexia, and may include optic atrophy, demyelinating sensorimotor neuropathy, urinary incontinence, and thinning of the corpus callosum. Few affected families have been described worldwide.[4] [5] We present a new case of SPG57.

A 14-year-old boy presented at 10 months of age with a history of spastic tetraplegia and a presumed diagnosis of cerebral palsy. He is the second child of non-consanguineous parents. He was born at full term following an uneventful pregnancy and delivery. His older sister has a diagnosis of incontinentia pigmenti, resulting from a de novo mutation causing exon 4 to 10 deletion of the inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase gamma (IKBKG) gene (MIM 300248).

The patient never achieved the ability to sit, stand, or walk independently. His neurological examination revealed axial weakness and spastic tetraplegia; the spasticity was more prominent in the lower than upper extremities. The patient presented generalised spikes and waves in the EEG, but without 3 hz amplitude. Therefore, categorize these episodes as typical absence seizures would be inaccurate. He began treatment with valproic acid, which was withdrawn after 2 years without further seizures. He achieved bowel and bladder control at 3 years of age but developed urinary retention by age five, which required bladder catheterization. At 6 years of age, he developed both bowel and bladder incontinence. His ophthalmology exam showed a progressive papilla excavation with temporal optic disc pallor. He was diagnosed with severe optic atrophy at the age of 13. His spasticity was progressive over time and required treatment with botulinum toxin and physiotherapy.

Several neurometabolic investigations were repeatedly normal. Nerve conduction studies demonstrated a chronic neurogenic pattern with mild demyelination. Magnetic resonance imaging of the brain showed thinning of the corpus callosum, white matter periventricular hyperintensities, and frontal horn asymmetry ([Fig. 1]). His muscle biopsy was normal. Genetic testing with karyotype and Array CGH were normal.

Fig. 1 Brain magnetic resonance imaging findings. (A) Thinning of the corpus callosum. (B) Mild periventricular hyperintensities with frontal horn asymmetry.

At the age of 15 years, clinical whole exome sequencing identified homozygous likely pathogenic recessive missense mutations involving exon 2 of the TFG gene; (NM_001195478.1):c.65G > A (p.Arg22Gln), associated with spastic paraplegia type 57 (SPG57). Genetic targeted testing showed a heterozygous mutation in the same gene in both parents and his sister.

Spastic paraplegia type 57 is a rare condition,[6] with an autosomal recessive inheritance pattern and progressive pyramidal tract involvement with an early onset and a variable degree of motor neuronal demyelination in addition to motor axonal degeneration.[5] [6] Brain MRI changes may include thinning of the corpus callosum, white matter hyperintensities, and cerebellar atrophy.[4] [5] Clinical exome sequencing has helped identify several genetic etiologies for cerebral palsy with a diagnostic yield that exceeds 50%. Therefore, some authors have suggested the next-generation sequencing first-line for diagnosis in cases of cryptogenic cerebral palsy.[7] Diagnosis of these conditions gives a better understanding of the disease, prognosis, and anticipated complications. It also offers to families the possibility of genetic counseling to assist with family planning.

In our patient, the progressive evolution of his condition, the presentation of new symptoms such as optic atrophy, polyneuropathy, loss of bladder and bowel control, and brain MRI findings (thinning of the corpus callosum), prompted a thorough investigation to determine the etiology. We present a rare type of HSP mimicking cerebral palsy.

Note

The procedures employed were reviewed and approved by the appropriate institutional review committee.

Publication History

Received: 19 April 2021

Accepted: 09 June 2021

Article published online:
23 July 2021

• References

• 1 Blackstone C. Cellular pathways of hereditary spastic paraplegia. Annu Rev Neurosci 2012; 35: 25-47
• 2 Fink JK. Hereditary spastic paraplegia: clinico-pathologic features and emerging molecular mechanisms. Acta Neuropathol 2013; 126 (03) 307-328
• 3 Tesson C, Koht J, Stevanin G. Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology. Hum Genet 2015; 134 (06) 511-538
• 4 Beetz C, Johnson A, Schuh AL. et al. Inhibition of TFG function causes hereditary axon degeneration by impairing endoplasmic reticulum structure. Proc Natl Acad Sci USA 2013; 110 (13) 5091-5096
• 5 Elsayed LEO, Mohammed IN, Hamed AAA. et al. Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan. Eur J Hum Genet 2016; 25 (01) 100-110
• 6 Miyabayashi T, Ochiai T, Suzuki N. et al. A novel homozygous mutation of the TFG gene in a patient with early onset spastic paraplegia and later onset sensorimotor polyneuropathy. J Hum Genet 2019; 64 (02) 171-176
• 7 Rosello M, Caro-Llopis A, Orellana C. et al. Hidden etiology of cerebral palsy: genetic and clinical heterogeneity and efficient diagnosis by next-generation sequencing. Pediatr Res 2021; 90 (02) 284-288