A number sign (#) is used with this entry because autosomal recessive spastic paraplegia-35 with or without neurodegeneration (SPG35) is caused by homozygous or compound heterozygous mutation in the FA2H gene (611026), which encodes fatty acid 2-hydroxylase, on chromosome 16q23.

Autosomal recessive spastic paraplegia-35 (SPG35) is a complicated form of SPG characterized by childhood onset of gait difficulties due to progressive spastic paraparesis, dysarthria, and mild cognitive decline associated with leukodystrophy on brain imaging. Other variable neurologic features, such as dystonia, optic atrophy, and seizures may also occur (summary by Dick et al., 2010). In addition, some patients with mutations in the FA2H gene have radiographic evidence of neurodegeneration with brain iron accumulation (NBIA), thus expanding the phenotype. Kruer et al. (2010) referred to this phenotypic spectrum of disorders as fatty acid hydrolase-associated neurodegeneration (FAHN).

In a detailed report of 19 patients with biallelic FA2H mutations, Rattay et al. (2019) stated that the phenotype was diagnostically consistent with a complicated form of SPG. The authors concluded that FA2H mutations cause a narrow phenotype despite prior attempts to classify it into separately defined disease entities.

For a discussion of genetic heterogeneity of autosomal recessive spastic paraplegia, see SPG5A (270800).

Dick et al. (2008) identified a large consanguineous Omani family in which 7 individuals had spastic paraplegia. Affected individuals presented between 6 and 11 years with foot drop and difficulty walking. There was rapid progression over the following 2 to 4 years with steadily increasing lower and then upper limb spasticity with hyperreflexia and extensor plantar responses, resulting in complete dependence by age 25. Variable features included dysarthria, ankle clonus, and increased muscle tone in the lower limbs. Two individuals had minor well-controlled seizures, 1 had urinary frequency and nocturnal enuresis, and most had progressive cognitive decline. Brain MRI of the proband showed no abnormalities. Four patients became wheelchair-bound in early adulthood, and the disorder made normal schooling impossible. Dick et al. (2010) provided follow-up of the family reported by Dick et al. (2008). Brain MRI of 1 affected individual at age 9 years showed T2 hyperintense lesions in the parietal and occipital periventricular white matter as well as scattered subcortical T2 hyperintensities.

Edvardson et al. (2008) reported 2 sisters, from a consanguineous Arab Muslim family, who developed walking difficulties due to spasticity at ages 4 and 6 years, respectively. Brain MRI in 1 was normal; brain MRI was not performed in the other child. There was no disease progression by ages 12 and 10, respectively. Edvardson et al. (2008) considered the phenotype in these patients to be consistent with a form of hereditary spastic paraplegia, and noted that SPG35 maps to chromosome 16q, close to the FA2H gene.

Edvardson et al. (2008) reported 7 patients from 2 consanguineous Arab Muslim families who presented at age 4 to 6 years with lower limb spasticity and gait disturbance after normal early childhood development. There was rapid progression of the disorder, with generalized dystonia, upper limb spasticity, dysarthria, and cognitive decline with loss of ability to read and write. Five of the 7 became wheelchair-bound by age 14 years. Other features included cerebellar signs with dysmetria and dysdiadochokinesis, and extensor plantar responses. Visual evoked potentials were delayed in 1 patient who was tested, suggesting a demyelinating process. Brain MRI of several affected individuals from both families revealed prolonged relaxation time of the posterior periventricular white matter, which progressed to involve the posterior limbs of the internal capsules and the corticospinal tracts. There was thinning of the corpus callosum and the pons, as well as cerebellar atrophy. Sural nerve biopsy was essentially normal, suggesting sparing of peripheral myelin. Edvardson et al. (2008) noted that the phenotype in these 2 families was consistent with a form of complicated SPG, but emphasized the MRI findings, and suggested that it should also be regarded as a new form of leukodystrophy.

Dick et al. (2010) reported a consanguineous Pakistani family in which 4 individuals had SPG35. The proband developed gait disturbances due to spastic paraparesis at age 4 years, and became wheelchair-bound at age 10. She also developed progressive dysarthria, bilateral optic atrophy, ophthalmoplegia, and dystonia. She had a low IQ of 59, attributable mainly to a hypoxic episode in infancy. However, other affected family members were reported to have a similar disorder with cognitive defects, and 2 had died at a young age. Brain MRI of the proband showed T2 hyperintensities in the white matter, involving the internal capsules, cerebrum, and cerebellum. There was atrophy of the corpus callosum, brainstem, and cerebellum.

Kruer et al. (2010) reported 3 Italian brothers from a consanguineous family who presented with gait impairment and frequent falls due to spastic paraplegia between ages 4 and 5 years. The disorder was progressive, with later development of ataxia, dysmetria, spastic quadriparesis, optic atrophy, ocular apraxia, dysarthria, and scoliosis. Two died from respiratory complications in their late twenties, and 1 developed seizures. Cognition was relatively preserved. Two brothers from an Albanian family had a similar disorder, with mild cognitive impairment, dystonia, dysarthria, and bladder and bowel incontinence. Brain imaging in 1 brother from each family showed T2 hypointensity in the globus pallidus bilaterally, consistent with iron deposition. There was also pontocerebellar atrophy, mild generalized cortical atrophy, thinning of the corpus callosum, and periventricular T2 white matter hyperintensities. On retrospective brain image analysis of a patient reported by Edvardson et al. (2008) and Dick et al. (2010), Kruer et al. (2010) noted that both patients also had evidence of brain iron accumulation in the globus pallidus.

Pierson et al. (2012) reported a 10-year-old boy, born of unrelated parents, with a complicated form of SPG35. The patient developed normally until age 3 years, when he developed progressive neurodegeneration following a febrile illness. He had lower extremity weakness and atrophy, spasticity, dystonic foot inversion, and poor balance. He also had dysarthria, neck weakness, mask-like facies, hunched posture, and mild cognitive deficits, but did not have optic atrophy or seizures. Serial brain MRIs showed progressive neurodegenerative changes, with white matter abnormalities, cerebellar and brainstem atrophy, thin corpus callosum, and evidence of demyelination. He also had an axonal sensory neuropathy. High-throughput sequencing identified compound heterozygosity for a missense mutation and deletion involving the FA2H gene (611026.0007 and 611026.0008).

Rattay et al. (2019) reported 19 patients from 16 unrelated families with FAHN/SPG35 associated with biallelic mutations in the FA2H gene. The patients were ascertained from several large cohorts through collaborative efforts after exome sequencing identified the mutations. Gait abnormalities started in early childhood at a mean age of 4 years in all but 2; the latter 2 showed onset at 10 and 20 years. The disorder was progressive, and patients became wheelchair-bound after a median duration of 7 years. Prominent features included spastic tetraparesis with lower limb predominance and variable truncal instability and oculomotor abnormalities with cerebellar characteristics, such as saccadic pursuit, slowed saccades, and gaze-evoked nystagmus. Many (60%) had exotropia in the absence of visual impairment. Other features included limb ataxia (71%), dysarthria (88%) or anarthria (later), and dysphagia (71%). About 50% of patients had movement abnormalities, mostly rigidity and dystonia. Most (93%) had mild cognitive deficits. Less common features included optic atrophy, rare seizures (3 patients), and mild sensory involvement. Some patients had abnormal neurophysiologic studies, including absent motor evoked potentials in the lower limbs, abnormal sensory evoked potentials, and prolonged visually evoked potentials. However, conduction velocities were normal, suggesting an axonal process. Peripheral neuropathy was present in 3 of 11 patients studied. Brain imaging reviewed retrospectively in 13 patients showed T2-hyperintense white matter lesions in the periventricular white matter, mild hypointense signals in the basal ganglia that could represent iron deposition, cerebellar atrophy, pontine atrophy, and supratentorial atrophy with thin corpus callosum. The authors suggested the 'WHAT' acronym, for white matter changes, hypointensity of the globus pallidus, pontocerebellar atrophy, and thin corpus callosum, to refer to the imaging findings. A notable feature was unusually bristly hair that showed abnormal longitudinal grooves, sometimes with plaques. Rattay et al. (2019) stated that the phenotype in their cohort was diagnostically consistent with complicated SPG, and concluded that FA2H mutations caused a narrow phenotype despite prior attempts to classify it into separately defined disease entities.

The transmission pattern of FAHN/SPG35 in the families reported by Rattay et al. (2019) was consistent with autosomal recessive inheritance.

By genomewide linkage analysis of an Omani family with autosomal recessive spastic paraplegia, Dick et al. (2008) identified a homozygous candidate region on chromosome 16q21-q23.1 between markers rs149428 and rs9929635 (maximum multipoint lod score of 4.86). This 20.4-Mb (3.25-cM) region, designated SPG35, cosegregated with disease status and was not homozygous in the unaffected family members. Genetic sequencing excluded mutations in the VPS4A (609982) and DYNC1LI2 (611406) genes.

In affected members of 2 unrelated consanguineous families with complicated spastic paraparesis and leukodystrophy, Edvardson et al. (2008) identified a homozygous mutation in the FA2H gene (611026.0001). Affected individuals from a third family with spastic paraparesis were found to have a different homozygous mutation in the FA2H gene (611026.0002). The relatively late onset of the disorders was consistent with the proposed need for FA2H at later stages of myelin maturation.

In affected members of an Omani family (Dick et al., 2008) and a Pakistani family with complicated SPG35, Dick et al. (2010) identified 2 different homozygous mutations in the FA2H gene (611026.0003 and 611026.0004, respectively). The findings indicated that mutations in FA2H are associated with SPG35, and that abnormal hydroxylation of myelin galactocerebroside lipid components can lead to a severe progressive phenotype, with a clinical presentation of complicated SPG and radiological features of leukodystrophy.

Kruer et al. (2010) identified 2 different homozygous mutations in the FA2H gene (611026.0005 and 611026.0006) in affected members from 2 unrelated families with progressive complicated spastic paraplegia associated with brain iron deposition in the globus pallidus. The authors noted the connection between leukodystrophy and neurodegeneration with brain iron accumulation.

In 19 patients with SPG35, Rattay et al. (2019) identified biallelic mutations in the FA2H gene. There were nonsense, frameshift, and missense mutations that mostly affected conserved residues and segregated with the disorder in the families. Functional studies of the variants were not performed. There were no apparent genotype/phenotype correlations.

Drecourt et al. (2018) found that cells derived from patients with FA2H mutations showed a significant increase (10- to 30-fold change) in cellular iron content when incubated with iron compared to controls. In response to high iron, patient cells showed a normal and appropriate decrease in transferrin receptor (TFRC; 190010) mRNA levels, but the amount of TFRC did not decrease in patient cells, suggesting impaired posttranslational lysosomal-based degradation of TFRC. Patient cells showed impaired transferrin (190000) and TFRC trafficking and recycling compared to controls, with clustering at the surface and in the perinuclear region, as well as abnormally enlarged lysosomes. Patient cells also showed decreased palmitoylation of TFRC, which is necessary for regulating TFRC endocytosis. Addition of the antimalarial agent artesunate rescued abnormal TFRC palmitoylation and decreased iron content in cultured patient fibroblasts. Similar findings were observed in studies of cells from NBIA patients due to mutations in other NBIA-associated genes. Drecourt et al. (2018) concluded that these forms of NBIA result from defective endosomal recycling and should be regarded as disorders of cellular trafficking, whatever the original genetic defect.

Donkervoort et al. (2014) identified a homozygous 2-bp deletion in the FA2H gene (c.509_510delAC; 611026.0006) in a brother and sister from Montenegro with SPG35. Both children had typical features of the disorder, but no brain iron accumulation was seen on brain MRI. Donkervoort et al. (2014) noted that this mutation had been identified by Kruer et al. (2010) in 2 brothers from Albania who had a similar neurodegenerative disorder with brain iron accumulation, suggesting that it may represent a founder mutation in individuals from the Balkan region. The findings indicated that additional factors likely contribute to phenotypic variability in this disorder.

Liao et al. (2015) identified pathogenic biallelic mutations in the FA2H gene in 3 patients from 2 unrelated Chinese families with SPG35. The patients were ascertained from a larger cohort of 97 probands with autosomal recessive SPG who underwent direct sequencing of the FA2H gene; mutations in several common forms of autosomal recessive SPG had been excluded in these patients. The phenotype was similar to that previously reported: patients had onset of progressive spasticity of the lower limbs in the first or second decade and variable cognitive impairment. The patient with no family history also had ocular motility deficits, ataxia, and seizures. Liao et al. (2015) concluded that SPG35 accounts for 2.1% of autosomal recessive SPG in the Chinese population.