A Rare Case of Fatty Acid Hydroxylase‐Associated Neurodegeneration in a Pakistani Boy With a Homozygous FA2H Variant

ABSTRACT

Fatty acid hydroxylase‐associated neurodegeneration (FAHN) is an ultra‐rare neurological disorder caused by a mutation in the FA2H gene. Defective production of this gene leads to abnormal myelin formation, which subsequently causes neurodegeneration and brain iron accumulation. This case report presents the case of a 7‐year‐old boy from Pakistan who was born to consanguineous parents. The initial symptom presented at two and a half years of age with seizures. His clinical course progressively worsened, manifesting as gait disturbances, dystonia, and regression of milestones. By the age of 7, he was unable to walk without support. On examination, the patient had a spastic diplegic gait with plantarflexion contracture in both lower limbs. Brain Magnetic Resonance Imaging (MRI) findings reported abnormal T2‐weighted hyperintensities, predominantly involving the parietal white matter, which is suggestive of FAHN. Finally, the diagnosis was confirmed by genetic analysis with the identification of a strong homozygous c.704G>A (p.Arg235 His) missense mutation in the FA2H gene.

Key Clinical Message

Patients presenting with spastic diplegia, gait abnormalities, seizures, dystonia, dysarthria, cognitive impairment, and confluent T2‐weighted white matter hyperintensities should be evaluated for fatty acid hydroxylase‐associated neurodegeneration. Consistent physiotherapy should be encouraged, as it may improve mobility and functional outcomes for these patients.

1. Introduction

Hereditary spastic paraplegias (HSPs) are a group of rare, neurodegenerative disorders that primarily affect the corticospinal tract. HSP is characterized by progressive spasticity of the lower extremities with or without neurological manifestations [1]. More than 40 genes with over 70 different loci have been observed in autosomal recessive, autosomal dominant, and X‐linked patterns of HSP [2]. Spastic paraplegia 35 (SPG35) is a complicated phenotype of HSP caused by homozygous or compound heterozygous variants in the fatty acid 2‐hydroxylase (FA2H, OMIM 611026) gene [3]. Hallmarks symptoms of SPG35 include progressive gait abnormality, dysarthria, dysphagia, ataxia, gradual intellectual impairment, extrapyramidal disturbance, limb paraparesis, optic atrophy, and seizures [1, 4].

The FA2H gene encodes the fatty acid 2‐hydroxylase/FA2H enzyme, which is present in the endoplasmic reticulum of oligodendrocytes [3]. The primary function of this enzyme is to synthesize myelin galactolipids, such as galactosylceramide, sulfatide, and sphingolipid, by 2‐hydroxylation of free fatty acids [3]. Thus, FA2H plays a pivotal role in the maintenance of the myelin sheath. Myelin sheath insulates the axon and aids in signal transduction along the axons, and interacts with the extracellular environment [4]. Loss of FA2H in mice resulted in severe demyelination of the spinal cord and optic nerves; however, peripheral nerves were relatively spared [5]. This was accompanied by loss of axons and alterations in the distribution and size of Purkinje neurons [5].

In addition to SPG35, the FA2H mutation may also present with leukodystrophy and neurodegeneration with brain iron accumulation (NBIA). This diverse range of phenotypes is referred to as fatty acid hydroxylase‐associated neurodegeneration (FAHN) [4, 6, 7]. The pathophysiology of the disease has been explained concisely in Figure 1. Approximately only 60 cases with FA2H mutations, associated with 50 different variants, have been reported so far in the literature [6]. However, only a few instances have documented the elimination or reduction of enzyme activity resulting from deletions or missense mutations [4, 8].

FIGURE 1.

Pathophysiology of FAHN.

This article describes the case of a 7‐year‐old Pakistani boy who presented with spastic diplegia and seizure disorder. Genetic analysis identified a homozygous mutation in the FA2H gene. To the best of our knowledge, this is the second case of FAHN in a Pakistani family. This case report describes the clinical features, diagnostic findings, and management plans of the patient. FAHN is an ultra‐rare disease, and our clinical understanding of it is limited. This case report provides significant insights that contribute to the current literature and will help medical professionals in establishing a diagnosis for patients with this condition.

2. Case History/Examination

A 7‐year‐old boy presented with progressive spastic diplegia in his lower extremities and recurrent seizures. He was the firstborn to consanguineous parents. He was born healthy at 36 weeks of gestation through cesarean section. The boy achieved developmental milestones and was able to walk without support at 14 months of age. He had a healthy younger brother who was 3 years old. His youngest sister was delivered stillborn. There was no prior history of the condition among other family members.

Since two and a half years of age, the boy started experiencing recurrent episodes of seizures, associated with loss of consciousness and rolling of eyes. These episodes were not associated with fetal or urinary incontinence. At 3 years of age, he developed a tiptoe gait, which caused difficulty in walking and frequent falls. At age four, abnormal gaze movements were noted. He exhibited progressive cognitive decline and regression of milestones by the age of five. He also had dystonia, characterized by involuntary muscle contractions in all four limbs. His speech was slurred, and he used hand gestures to converse. The patient did not have dysphagia or fecal or urinary incontinence.

A neurological examination of the patient revealed hyperreflexia and ankle clonus in his lower limbs with a positive Babinski sign. Plantarflexion contracture was present in both lower limbs. Moreover, he had a spastic diplegic gait and was unable to ambulate without assistance. Table 1 presents a concise timeline of the patient's signs and symptoms.

TABLE 1.

Timeline of patient's signs and symptoms.

Year	Signs and symptoms
2 and a half years	Recurrent episodes of seizures
3 years	Tiptoe gate, difficulty in walking, frequent falls
4 years	Abnormal gaze movements
5 years	Cognitive decline, regression of milestones, dystonia, slurred speech
7 years	Unable to walk without assistance

3. Methods (Differential Diagnosis, Investigations, and Treatment)

3.1. Investigations

A thorough workup, including complete blood count (CBC), renal function tests, liver function tests, electrolytes, thyroid function tests, serum lactate, homocysteine levels, urine organic acids, and plasma amino acids, was advised to screen for any metabolic causes, electrolyte disturbances, thyroid disorders, mitochondrial diseases, and aminoacidopathies. However, all test results came back normal except for the presence of mild anemia. Electroencephalography (EEG) reported a generalized seizure disorder. Magnetic Resonance Imaging (MRI) findings reported abnormal signal intensity areas in bilateral symmetrical periventricular white matter. Predominantly, the parietal region appeared hypotense in T1W and hypertense on T2W/FLAIR sequences.

3.1.1. Genetic Analysis

While the clinical picture and MRI findings were suggestive of FAHN, whole‐exome sequencing (WES) was performed to reach a definitive molecular diagnosis, identify the pathogenic variant responsible for causing the disease, and facilitate accurate genetic counseling for the parents to discuss prognosis, disease course, and management options. Genetic analysis identified a strong homozygous c.704G>A (p.Arg235 His) missense variant in the FA2H gene located on exon 5/7. The reported variant is predicted to cause a change in the amino acid Arginine to Histidine at codon 235. Diagnosis of autosomal recessive fatty acid hydroxylase‐associated neurodegeneration was made based on clinical features and genetic findings. Table 2 summarizes the genetic findings.

TABLE 2.

Genetic findings identified on WES.

Characteristic	FA2H
Gene	FA2H
HGVS nomenclature a	c.704G>A
Protein change	p.Arg235His
Location	exon 5/7
Zygosity	Homogenous
Function	Missense
gnom AD allele frequency	0.0002
Impact	High
REVEL a Score	0.881
CADD a (PHRED)	29.1
Clinical significance/ACMG a classification	Uncertain significance

Note: A homozygous c.704G>A (p.Arg235 His) missense variant in the FA2H gene was identified. A gnom AD allele frequency of 0.0002 explains the rarity of this variant in population databases. Based on in silico prediction tools (REVEL score of 0.881 and CADD PHRED score of 29.1), it can be predicted that this variant has a deleterious effect on protein function. Moreover, in accordance with the guidelines by the American College of Medical Genetics and Genomics (ACMG) this is a variant of uncertain significance. However, given the clinical presentation and neuroimaging findings, this variant was considered a plausible explanation for the disease. Source: Patient's genetic report. ACMG = American College of Medical Genetics and Genomics, CADD (PHRED) = Combined Annotation Dependent Depletion scoring, ranging from 1 to 99, HGVS = Human Genome Variation Society.

^a REVEL score (combination from 13 individual tools; ranges from 0 to 1) = higher scores reflect greater likelihood that variant is disease‐causing.

3.2. Management

Treatment of FAHN is mostly supportive. The medical regimen of the patient included Baclofen and Tizanidine to achieve muscle relaxation and Lacosamide, an anti‐epileptic drug. Physiotherapy and speech therapy were initiated promptly.

At the next follow‐up visit, the patient demonstrated slight improvements. He was able to stand and walk a few steps independently after undergoing physiotherapy. Moreover, he had no episodes of seizures in this period. The patient's condition is currently being monitored with regular follow‐ups.

4. Discussion

The case report describes the case of a Pakistani boy with characteristic findings of FAHN. This is not the first occurrence of the disease in Pakistan. In 2010, Dick et al. reported a case of FA2H mutation (homozygous p.Arg53_Ile58del) in a Pakistani family [4]. Four members of the family were affected and exhibited typical symptoms of HSP, dystonia, impaired cognition, and seizures [4].

Our patient had a c.704GNA; p.Arg235 mutation in the FA2H gene. Data from the ExAC/GnomAD and 1000 Genomes databases show that this mutation is most commonly found in South Asia [9]. However, Magariello et al. reported a case of a heterozygous p.Arg235His point mutation in an Italian male [9]. This mutation was again detected by Rattay et al. in a large cohort of 19 FAHN/SPG35 patients [6]. The FA2H gene contains two domains, a fatty acid hydroxylase domain and a cytochrome b5 heme‐binding domain. The p.Arg235His mutation occurs on the hydroxylase domain and is therefore likely to affect the process of hydroxylation [9].

This disease commonly occurs during early childhood, between the ages of 3 and 5 years [10]. This was consistent with our patient, who presented with initial neurological symptoms near the age of 3. The rate of progression and severity of symptoms show variability among patients. For many individuals, gait impairment worsens gradually. It is more pronounced during adolescence and then slows down after 5–10 years of impairment. It eventually reaches a plateau after which the worsening of gait‐related symptoms decreases [1].

Over 30% of patients with FAHN experience epileptic seizures [6]. This aligns with our patient's case, presenting with recurrent seizures from early childhood. This was also true for the case of the Pakistani girl reported by Dick et al. [4]. In another study, Liao et al. also reported the occurrence of epilepsy in a Chinese patient with a homozygous p.Leu77Arg mutation [8]. Furthermore, approximately 90% of patients exhibit a decline in their intellectual abilities [6]. This aligns with our findings, as well as those of Dick et al., who reported an Omani male with a homozygous p.Arg235Cys mutation presenting with symptoms of cognitive decline [4].

Spastic tetraparesis, dysarthria, and dysphagia are typical symptoms with a reported prevalence of over 90% [6]. Our patient demonstrated spastic paresis in his lower limbs and had impaired speech articulation. However, our patient did not show any signs of dysphagia. Although fecal and urinary incontinence are frequently reported symptoms, they were not observed in our patient. Classic MRI findings of FAHN include T2 hyperintense white matter abnormalities with parietal predominance [6]. These findings match our case. Other common MRI findings include hypointensity of the globus pallidus, thinning of the corpus callosum, atrophy of the cerebral hemispheres, vermis, supratentorial region, and pons [6].

5. Conclusion

This report details a case of FAHN in a Pakistani boy who was born to consanguineous parents. Genetic analysis of the patient revealed a homozygous missense mutation (c.704G>A; p.Arg235His) in the FA2H gene. The boy presented with classic FAHN symptoms, such as spastic diplegia, gait abnormality, seizures, dystonia, dysarthria, and cognitive impairment. Our patient showed limited but encouraging improvement in his gait with physiotherapy. This finding emphasizes the crucial role of sustained physiotherapy in improving outcomes for such patients. This report also highlights the impact of parental consanguinity on the manifestation of rare inherited phenotypes. In a country like Pakistan, where rates of intra‐familial marriages remain high, preconception genetic testing and counseling of parents must be prioritized [11]. The aforementioned FA2H variant in our report has been previously documented twice in the literature and is particularly prevalent among individuals of South Asian descent. This article enhances current knowledge of this rare neurodegenerative disorder and aims to aid physicians in diagnosis.

Author Contributions

Araj Naveed Siddiqui: conceptualization, investigation, writing – original draft, writing – review and editing, visualization, validation. Yamna Naveed Siddiqui: conceptualization, investigation, writing – original draft, writing – review and editing. Noor ul Huda Abbasi: conceptualization, investigation, writing – original draft, writing – review and editing. Raman Kumar: supervision, validation, writing – review and editing, writing – original draft. Hermann Yokolo: writing – review and editing, writing – original draft, investigation.

Funding

The authors have nothing to report.

Ethics Statement

Our institute does not require ethical approval for reporting a case report.

Consent

Written consent from the patient's guardian was obtained for the patient's anonymized information to be published in this article.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

All data relevant to the study are included in the article.