Hrev_master Healthcare in Low-resource Settings 2025; volume 13:13440 Novel clinical findings of neurodevelopmental disorder linked to HPDL gene mutation: a case report from Saudi Arabia Abdullah Musallam Alkhalaf,1 Moayad Ahmed Alshaqaq,2 Nadia Jradi,3 Ahmad Hassan Aljaziri,1 Essa Sultan Alsultan1 1College of Medicine, King Faisal University, Al-Ahsa; 2Pediatric Neurology Consultant, Maternity and Children Hospital, Al-Ahsa; 3Department of Pediatrics, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia Abstract HPDL gene mutations have recently been linked to neurode- velopmental disorders with variable presentations, ranging from mild hereditary spastic paraplegia to severe infantile neurodegen- eration. While the HPDL protein’s role is unknown, it is highly expressed in brain mitochondria. Here we report a case of a 19- month-old male with a homozygous HPDL gene mutation present- ed with global developmental delay, epilepsy, laryngomalacia post-arytenoidectomy, swallowing dysfunction, and spasticity. He exhibited significant dysmorphic features and recurrent convul- sions, and required nasogastric feeding due to oral feeding diffi- culties. Introduction The pathophysiology of neurodevelopmental impairments is complicated and involves both hereditary and environmental vari- ables. These disabilities arise from improper development of the central nervous system. Recent research has demonstrated that biallelic variations in the 4-Hydroxyphenylpyruvate Dioxygenase- like (HPDL) gene may be the cause of neurodevelopmental disor- ders.1 Biallelic variants in the HPDL gene have been described in 2020 as able to cause a progressive disorder with variable clinical presentation, ranging from milder manifestation of adolescent- onset pure Hereditary Spastic Paraplegia (HSP), classified as Autosomal recessive spastic paraplegia-83 (SPG83), to severe Neonatal-Onset Encephalopathy or infantile-onset Neurodegeneration with progressive Spasticity and brain White Matter Abnormalities (NEDSWMA).2 Furthermore, affected patients with HPDL mutation typically develop spasticity, primar- ily in the lower limbs.3 Still, the role of the HPDL protein remains unknown. HPDL is broadly expressed in tissues, with the most concentrated amounts found in the brain, and it is specifically located in mitochondria.4 Here, we report a patient with a novel clinical manifestation linked to an HPDL mutation. Comprehending these genetic foun- dations is essential for enhancing diagnostic precision and possi- bly directing treatment approaches in the future. This study was approved by the Ethics Committee of Maternity and Children’s Hospital – Al Ahsa, with the IRB reference number (H-05-HS- 137). Written informed consent was obtained from the father. Case Report Hereby, we report a 19-month-old male with global develop- mental delay, epilepsy, laryngomalacia, S/p arytenoidectomy, swallowing dysfunction, spasticity, thin corpus callosum on MRI brain, and confirmed homozygous HPDL gene mutation on genet- ic testing. Detailed history taking reveals a full-term male infant who was born at 38 weeks of gestation to healthy first-degree cousins. The course of the pregnancy was uneventful. APGAR score was eight at 1 minute and 5 minutes. The delivery was complicated by meconium-stained amniotic fluid, leading to respiratory distress that resolved post-delivery. At birth, the infant presented with sev- eral dysmorphic features, including low-set ears, a depressed nasal bridge, micrognathia, clinodactyly, fixed flexion of the proximal interphalangeal joints of the 4th fingers bilaterally, and rocker-bot- tom feet. The family consists of nine children in total, including the patient, who is the only one currently confirmed to have the dis- ease. Two of the siblings, previously diagnosed with idiopathic brain atrophy of unknown etiology, are deceased. The remaining six children are alive and exhibit normal neurodevelopment. Whole Exome Sequencing (WES) has not been performed on any of the children. Initial physical examination showed dysmorphic infant vitally Correspondence: Nadia Jradi, Department of Pediatrics, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia Tel.: +966.569208088. E-mail: Nadia.jradi@kfu.edu.sa Key words: HPDL gene mutation, neurodevelopmental delay, spasticity, hypotonia, genetic neurodevelopmental disorders. Conflict of interest: the authors do not have any conflict of interest or funding source to declare. Ethics approval and informed consent to participate: this study was approved by the Ethics Committee of Maternity and Children’s Hospital – Al Ahsa, with the IRB reference number (H-05-HS-137). Written informed consent was obtained from the father. Availability of data and materials: all data underlying the findings are fully available. Received: 29 November 2024. Accepted: 10 June 2025. Early access: 8 September 2025. This work is licensed under a Creative Commons Attribution 4.0 License (by-nc 4.0). ©Copyright: the Author(s), 2025 Licensee PAGEPress, Italy Healthcare in Low-resource Settings 2025; 13:13440 doi:10.4081/hls.2025.13440 Publisher's note: all claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organi- zations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher. [page 244] [Healthcare in Low-resource Settings 2025;13:13440] stable. CNS examination showed open anterior fontanelle, a head circumference of 36 cm, high muscle tone (spasticity) in all extremities, axial hypotonia, Asymmetrical Moro reflex (sluggish on the left side) Intact, sucking, palmar, and plantar reflexes. Left upper limb internally rotated, extended at the elbow, flexed at the wrist with reduced movement. All other extremities moved freely. Chest, cardiovascular, and gastrointestinal were normal. Laboratory tests were unremarkable. Cranial ultrasound and brain MRI showed a bilateral germinal matrix subependymal cyst. No white matter abnormalities were detected. EEG showed no evi- dence of epileptiform discharge. In the first month, the patient had axial hypotonia, poor head control, loss of ocular, pursuit and mild peripheral spasticity. By the second month, it was noted to have micrognathia, micro- cephaly (37 cm), peripheral spasticity, and central hypotonia. He developed recurrent episodes of convulsions, apnea, stridor, and cyanosis. Convulsions were in the form of generalized tonic-clonic movements. The EEG background shows diffuse slow 2-3 Hz delta activity, indicating a non-epileptiform pattern. The patient was then started on phenobarbitone. Genetic testing using Whole Exome Sequencing (WES) iden- tified a homozygous likely pathogenic variant in the HPDL gene, consistent with an autosomal recessive neurodevelopmental disor- der characterized by progressive spasticity and brain white matter abnormalities. The specific variant detected was HPDL, c.788C>G p. (Thr263Arg), which results in an amino acid substitution from threonine to arginine at position 263. At four months, the patient had global developmental delay and microcephaly. Although seizures were controlled, the episodes of frequent episodes of apnea with cyanosis and stridor persisted. The patient was then diagnosed to have laryngomalacia and under- went a micro laryngoscopy with arytenoidectomy. Apnea resolved after surgery. At eight months old, the patient still showed profound devel- opmental delay with no social smile, no sound imitation, and no interest in the surroundings. Axial hypotonia and peripheral spas- ticity increased in severity, with no improvement despite regular physiotherapy. Moreover, the patient failed to feed orally, which required feeding using a nasogastric tube. He then started to show a new form of abnormal movements while being on Levetiracetam. The EEG shows intermittent slow activity reflecting cerebral dys- function. Sandifer phenomenon secondary to GERD was suspect- ed; however, no fluoroscopic findings of GERD were detected on upper GI study, and the patient failed to improve on a one-month trial of omeprazole. Upper gastrointestinal endoscopy was then performed and revealed normal esophageal mucosa with a corkscrew appearance suggestive of diffuse esophageal spasm. Manometry studies were not available to confirm the diagnosis. The patient continues to be fed by nasogastric tube. Discussion Hereditary Spastic Paraplegia (HSP) is a collection of diseases that are mostly characterized by spasticity and paralysis in the lower extremities.5 Today, there are more than 80 distinct forms of HSP, including a broad spectrum of molecular and metabolic aeti- ologies, that can be inherited in an autosomal dominant, recessive, or X-linked fashion.6 In populations where there is parental con- sanguinity and/or a common set of founder mutations, autosomally recessively inherited illnesses are a significant source of both death and morbidity.7 Although the consanguinity rates in Western and European countries are less than 0.5%, this rate is much higher in Arab countries, reaching 20-50% of marriages in Saudi Arabia.8 Both spastic paraplegia 83 (SPG83) and a Neuro- Developmental Disease with progressive Spasticity and brain White Matter Abnormalities (NEDSWMA) are the two primary phenotypes that clinically describe the HPDL-related neurodegen- erative condition. SPG83 is characterized by spastic paraplegia in juveniles, whereas NEDSWMA often manifests as severe neurode- velopmental delay, brain atrophy, and spasticity in toddlers.1 Previous studies have shown that probands with HPDL variations and early disease start had either a milder clinical course with mild to severe developmental delay and spasticity progression, or a severe newborn encephalopathy with little to no psychomotor development. Adolescent-onset illness, on the other hand, has not been linked to developmental problems.4 The range of neuroradiological findings linked to variations in HPDL was likewise quite high. They varied from no pathological findings to anomalies in the striatum and white matter.9 Our case is the second reported HPDL gene mutation case in Saudi Arabia. The first case was reported by Wiessner et al. in 2021.6 The dysmorphic features reported in our case share certain similarities with other reported cases.6 However, our patient showed a set of unique dysmorphic features, including a depressed nasal bridge, micrognathia, clinodactyly, and rocker-bottom feet that were not previously reported. Other reported dysmorphic fea- tures, such as high-arched palates, hypertelorism and long philtrum were not detected in our case.6 The respiratory failure in this case was attributed to peripheral apnea caused by laryngomalacia. In contrast, the respiratory failure in the other reported cases was due to central apnea.6 Moreover, the highly suspected diagnosis of diffuse esophageal spasm is also a novel clinical finding, since it was not reported previously in similar patients. Although we acknowledge that Confirmation of the diagnosis with manometry studies is needed. Conclusions HPDL gene mutation is a rare white matter disease that typi- cally presents as spastic quadriplegia with central hypotonia. Our patient exhibited novel clinical findings, including diffuse esophageal spasm and laryngomalacia. Additionally, unusual dys- morphic features were observed, such as micrognathia, clinodacty- ly, a depressed nasal bridge, and rocker-bottom feet. References 1. Wang Y, Zheng X, Feng C, et al. HPDL mutations identified by exome sequencing are associated with infant neurodevelop- mental disorders. Mol Genet Genomic Med 2022;10:2025. 2. Sartorelli J, Longo D, Travaglini L, et al. Acute ophthalmople- gia with Wernicke-like MRI pattern in a patient with HPDL- related disorder. Mov Disord Clin Pract 2024;11:1160-2. 3. Husain RA, Grimmel M, Wagner M, et al. Bi-allelic HPDL variants cause a neurodegenerative disease ranging from neonatal encephalopathy to adolescent-onset spastic paraple- gia. Am J Hum Genet 2020;107:364–73. 4. Micule I, Lace B, Wright NT, et al. Case report: two families with HPDL related neurodegeneration. Front Genet Case Report [Healthcare in Low-resource Settings 2025;13:13440] [page 245] 2022;13:780764. 5. Yu H, Wei Q, Luo WJ, Wu ZY. Novel bi-allelic HPDL variants cause hereditary spastic paraplegia in a Chinese patient. Clin Genet 2021;100:777–8. 6. Wiessner M, Maroofian R, Ni MY, et al. Biallelic variants in HPDL cause pure and complicated hereditary spastic paraple- gia. Brain 2021;144:1422–34. 7. Morgan NV, Yngvadottir B, O’Driscoll M, et al. Evidence that autosomal recessive spastic cerebral palsy-1 (CPSQ1) is caused by a missense variant in HPDL. Brain Commun 2021;3:2. 8. Khayat AM, Alshareef BG, Alharbi SF, et al. Consanguineous marriage and its association with genetic disorders in Saudi Arabia: A review. Cureus 2024;16:e53888. 9. Numata-Uematsu Y, Uematsu M, Yamamoto T, et al. Leigh syndrome-like MRI changes in a patient with biallelic HPDL variants treated with ketogenic diet. Mol Genet Metab Reports 2021;29:100800. Case Report [page 246] [Healthcare in Low-resource Settings 2025;13:13440]