Expanding the spectrum of retinal dystrophy and leukodystrophy: Novel acyl-CoA binding domain-5 mutation with sensorineural deafness and hypergonadotropic hypogonadism

INTRODUCTION

Peroxisomes are membrane-bound subcellular organelles involved in the oxidation of organic acids, particularly fatty acids. Peroxisomal disorders are classified as peroxisomal biogenesis disorders which affect multiple enzymatic pathways or single peroxisomal enzyme deficiency (PED) disorders. PED disorders affecting β-oxidation of very long-chain fatty acids (VLCFA’s) are a rare group of disorders, of which X-linked adrenoleukodystrophy is the most common disorder.^[1] Acyl-CoA binding domain-5 (ACBD5) protein-related retinal dystrophy with leukodystrophy (RDLKD) is a recently described PED disorder with childhood onset progressive spastic paraparesis, cerebellar dysfunction, cone-rod dystrophy, and leukodystrophy on brain imaging. Here, we describe a novel ACBD5 mutation and the first case of RDLKD from south Asia, with additional features of ovarian failure and previously unreported sensorineural deafness.

CASE REPORT

A 17-year-old female, born to second-degree consanguineous parents with a normal birth and developmental history, began experiencing walking difficulties at the age of 3. Her mother had observed rapid, involuntary eye movements when she was 10 months old. She developed progressive symmetrical distal weakness, initially presenting as ankle instability and tripping while running, which then progressed to proximal symmetrical weakness. By the age of 13, her lower limbs were completely immobile due to spasticity and ankle contractures, and her mobility was further limited by truncal weakness. Over the past 3 years, she has had increasing difficulty lifting her arms and gripping objects. Her academic performance began to decline at the age of 6. In addition, her vision has been progressively worsening, and for the past 2 years, she has had speech difficulties characterized by undue pauses and a lack of word clarity. No other cranial nerve, bowel, bladder, or sensory complaints were reported. She reached menarche at 13 but has had amenorrhea for the past year. Her older brother was diagnosed with spastic cerebral palsy in childhood, and her younger sister passed away on the 2^nd day of life due to meconium aspiration [Figure 1].

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Figure 1:

Pedigree chart.

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On examination, she presented with dysmorphic facial features, including crowded truncated teeth and small palpebral fissures. The cognitive assessment was constrained due to visual impairments, intellectual disability, decreased attention, and dysarthria. Her visual acuity was diminished, and fundus examination showed bilateral diffuse disc pallor and macular pigmentation indicative of cone-rod dystrophy [Figure 2]. Extraocular movements were complete in all directions, yet there was bilateral mild esotropia and pendular nystagmus. The spino-motor evaluation revealed generalized muscle wasting, contracture of both tendo-achilles, symmetrical spastic weakness in all limbs (with the upper limbs at grade 3–4 power and the lower limbs at grade 0 power), truncal weakness, hyper-reflexic deep tendon reflexes, and bilateral extensor plantar responses. In addition, she exhibited impaired coordination in the upper limbs and scanning dysarthria.

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Figure 2:

Fundus examination showing diffuse disc pallor and a hyperpigmented atrophic patch at the macula (black arrow) with dystrophy. Features suggestive of cone-rod dystrophy.

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1.5T magnetic resonance imaging brain imaging revealed subtle T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities in the subcortical region with progressive diffuse supratentorial and infratentorial brain atrophy, compared to previous imaging at the age of 10 [Figure 3]. The posterior cortices seem more atrophied than anterior cortex with subtle subcortical T2-FLAIR hyperintensities. Marked atrophy was seen in the midbrain, pons, and cerebellum as well. Audiogram and evoked brainstem response indicated bilateral moderate sensorineural hearing loss. Otoacoustic emission evaluation suggested outer hair cell dysfunction. Nerve conduction study showed mild axonal neuropathy in the bilateral peroneal nerves. The patient exhibited hypergonadotropic hypogonadism, as indicated by elevated serum Follicle-Stimulating Hormone (FSH) at 147.59 mIU/mL, elevated Luteinizing Hormone (LH) at 33.72 mIU/mL, and low serum Estradiol (E2) at <11.80 pg/mL. Clinical exome sequencing (CES) identified an ACBD5 mutation with deletion of exons 10–12 on chromosome 10, a variant likely pathogenic for RDLKD.

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Figure 3:

Magnetic Resonance Imaging taken at (a) 10 years and (b) 17 years of age showing prominent midbrain, pons, and cerebellar (white arrows) atrophy. The posterior cortex is more atrophied than the anterior cortex. Subtle T2 / Fluid Attenuated Inversion Recovery hyperintensities are seen in the subcortical region and posterior limb of the internal capsule suggestive of leukodystrophy (red arrows).

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DISCUSSION

Peroxisomal functions of β-oxidation of fatty acids are carried out through crosstalk with other subcellular organelles such as mitochondria and endoplasmic reticulum (ER), through contact “tethering” proteins. The ER vesicle-associated membrane protein-associated protein A/B and peroxisomal acyl CoA binding domain protein 5 (ACBD5) tethering is the first step in transport of fatty acids into peroxisomes [Figure 4]. The peroxisomal ACBD5 protein is a membrane-bound receptor for VLCFA-CoA, with specific affinity for the C26:0–CoA. Defect in ACBD5 protein causes dysfunction at the level of VLCFA entry into the peroxisomes, thus affecting downstream β-oxidation.

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Figure 4:

Illustration showing peroxisome-endoplasmic reticulum tethering through acyl-CoA binding domain 5 (ACBD5) and vesicle-associated membrane protein-associated protein A/B proteins. The cytosolic acyl-CoA binding domain of ACBD5 captures and transfers very long-chain fatty acids-CoA into the peroxisome for oxidation by presenting C26-CoA to the ABCD1 transporter. CoA: Coenzyme-A, RDLKD: Retinal Dystrophy with Leukodystrophy, VAPB: Vesicle-Associated-membrane Protein-associated protein B, ACBD5: Acyl-CoA-Binding Domain-containing protein 5, VLCFA-CoA: Very-Long-Chain Fatty Acid Coenzyme-A, X-ALD: X-linked Adrenoleukodystrophy, ACOX-1: Acyl-CoA Oxidase 1, DBP: D-Bifunctional Protein, SCP2: Sterol Carrier Protein-2, ABCD1: ATP-Binding Cassette sub-family D 1.

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ACBD5-related RDLKD is a recently identified PED disorder, extremely rare with only a few cases documented.^[2-7] ACBD5 mutation was first discovered as a novel disease gene candidate in three siblings presenting with cone-rod dystrophy, spastic paraparesis, and white matter disease.^[2] Common clinical features reported in subsequent homozygous AR variants are that of cone rod dystrophy, delayed or regressive motor development, spastic paraparesis, ataxia, and leukodystrophy. Late-onset symptoms include dysarthria, cognitive and urinary dysfunction, while facial dysmorphisms, cleft palate, microcephaly, bony dysplasia, seizures, ovarian insufficiency, and dystonic head tremor have been reported sporadically. Abu-Safieh et al.^[2] identified a variant (c.1205 + 1G>A, p.Gly402Aspfs5) in three siblings, leading to a truncating mutation and significant protein instability. A frameshift variant (c.626-689_937– 234delins936 + 1075_c.936 + 1230inv) resulting in the loss of exons 7 and 8 and the absence of ACBD5 protein, along with a novel nonsense variant (c.1467G>A, p.Trp489*) in exon 12 of 13, has also been reported.^[3,4] Gorukmez et al.^[5] reported a novel non-sense variant (c.1297C>T, p.Arg433*) in two siblings. Rudaks et al., recently described primary ovarian failure and dystonic tremor in a case with two pathogenic mutations leading to a nonsense variant (c.979G > T, p.Gly327*) and a deletional frameshift variant (c.399del, p.Ile134Leufs*6).^[6] Heterozygous variants were associated with restricted clinical features, such as retinitis pigmentosa and early foveal atrophy.^[7]

CES in our patient revealed a homozygous contiguous deletion of approximately 4.02 kb on chromosome 10 [chr10: g. (27197443_27204439)_(27208446_27210813) del], encompassing exons 10 to 12 of the ACBD5 gene, an unreported variant. This defective ACBD5 protein leads to impaired capture and transfer of VLCFA into the peroxisome for β-oxidation, resulting in impaired peroxisomal response and membrane growth. Hormonal assays for amenorrhea confirmed hypergonadotropic hypogonadism. In addition, our case presented a novel feature of sensorineural deafness. Accompanying leukodystrophy and brain atrophy, the T2/FLAIR hyperintensity in the posterior limb of the internal capsule was notable, similar to a previous case.^[3] Plasma VLCFA levels in RDLKD show elevation only in C26:0 level; however, the previous reported cases show varying levels and so they may not be always reliable.^[4] This may be attributable to the current uncertainties surrounding the functional role of ACBD5. Consequently, and in light of financial limitations, VLCFA quantification was not performed in our patient. Although a phenotypically distinct presentation of the same disease was suspected in the elder sibling, definitive confirmation was not possible due to the parents’ refusal to undergo genetic testing, including self-testing. From a genetic counselling perspective, consanguinity is recognized as a significant risk factor for autosomal recessive inheritance. Therefore, carrier parents should be advised to undergo genetic testing after being informed about the potential risk of transmitting the condition to their children.

CONCLUSION

ACBD5-related RDLKD is a rare entity and should be considered in patients with childhood-onset progressive cerebellar dysfunction, cone-rod dystrophy, spastic paraparesis, and leukodystrophy. Here, we report a novel ACBD5 variant, the first case from South Asia with a previously unreported feature of bilateral sensorineural hearing loss. This case advances the understanding of genetic variations and phenotypic presentations of ACBD5-related RDLKD.