Hereditary spastic paraplegia type 35 in a Turkish girl with fatty acid hydroxylase associated neurodegeneration

Hereditary spastic paraplegias (HSPs) are a rare form of neurodegenerative disorders that mainly affect the corticospinal tract. The hallmark signs of HSP include leg muscle stiffness and exaggerated reflexes, which ultimately result in spastic paralysis of the legs due to wasting of upper and distal limb muscles. Spastic paraplegia type 35 is an autosomal recessive HSP caused by compound heterozygous or homozygous mutations in the fatty acid 2-hydroxylase gene. FA2H variants in humans has been shown to be associated with not only SGP35 but also leukodystrophy and neurodegeneration with brain accumulation. Herein we report an eight year old Turkish girl with fatty acid hydroxylase-associated neurodegeneration (FAHN) having novel homozygous variant in FA2H gene. The patient admitted to the department of pediatric metabolism with complaints of spastic gait since the age of 7 years. Brain MRI demonstrated reduction of cerebellar volume. Subsequent whole exome sequencing identified a homozygous c.460 C>T missense mutation in FA2H gene. This mutation resulted in a homozygous p.R154C substitution in exon 3 of FA2H.

Case report

She was the second child born to healthy consanguineous Turkish parents. There was no family history of neurological disease except her uncles progressive gait disturbance and finally died at the age of 20 years. She was born at the gestational age of 37 weeks, and her birth weight was 2300 g. Pregnancy, birth and neonatal period proceeded unremarkably. She reached normal developmental milestones during infantile period and was able to walk at the age of 11 months. She developed a progressive gait disturbance at the age of 7 years. Her parents first noted tiptoes walking bilaterally. She was referred to pediatric metabolic unit due to 1-year history of spastic and ataxic gait at 8 years old. On physical examination, she had no dysmorphic features and neurological examination revealed increased muscle tone in lower limbs, bilateral ankle clonus and dysdiadochokinesis. She had frequent falls. Her legs crossed with ambulation. She began showing to deteriorate school performance. Basal metabolic work-up was nonspecific. Serum lipids and glucose were normal, as were lactate and pyruvate. Ferritin, ceruloplasmin, and copper levels were normal.

Enzyme activities of arylsulfatase-A, alpha and beta galactosidase, hexosaminidase A and B were within normal values. Brain MRI showed slight reduction in the cerebellar volume with no iron deposits (Figure 1). Her spastic paraplegia was progressive despite physiotheraphy. She has neither intellectual decline nor epileptic seizures. After obtaining written informed consent from the parents of the patient, whole exome sequencing was performed to determine the genetic cause of HSPs and identified a homozygous c.460 C>T missense mutation in FA2H gene. This mutation resulted in a homozygous p.R154C substitution in exon 3 of FA2H. The parents were heterozygous carriers.

Discussion:

Sphingolipids containing 2-hydroxylated fatty acids are vital components of the myelin sheath. This process of hydroxylation is mediated by the fatty acid 2-hydroxylase enzyme. Defect of FA2H results in deterioration of neuronal cells due to impaired myelination and leads to neuromuscular consequences. It is characterized by childhood onset spasticity, cognitive decline and leukodystrophy. In addition to typical features; seizures, dysphagia, dysarthria, dystonia, neuropathy, optic atrophy and brain iron accumulation were also observed. Neurodegeneration with brain iron accumulation (NBIA) consists of clinically and genetically heterogeneous group of disorders affecting both children and adults. Most common NBIA disorders are caused by mutations in PANK2, PLA2G6, C19orf12, WDR45. The rare NBIA disorders are caused by mutations in CoASY, ATP13A2 and FA2H. Cerebral iron accumulation is not a prominent feature in SGP35 caused by mutations in FA2H gene and is not always dependent on disease duration or severity. We report a patient with novel FA2H mutations without evidence of cerebral iron accumulation. No clear genotype-phenotype correlations are defined in the literature. Treatment is currently limited to symptomatic benefit and genetic counselling fort he family.

The current case underlies the useful role of exome sequencing in the genetic diagnosis of heterogeneous diseases like HSPs and enlarges the spectrum of mutations in FA2H gene. Cerebral iron accumulation is an inconstant finding in SGP35 and its absence should not discourage one from evoking this diagnosis.