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Ann Indian Acad Neurol
Ann Indian Acad Neurol
AIAN
Ann Indian Acad Neurol
Annals of Indian Academy of Neurology
0972-2327
1998-3549
Wolters Kluwer - Medknow India

AIAN-27-441
10.4103/aian.aian_962_23
Letters to the Editor
Spastic Paraparesis in Donnai–Barrow Syndrome: A Rare Case Report from India
Parida Swati *
Kumar Nikhil A. *
Chaurasia Rameshwar N.
Kumar Anand
Pathak Abhishek
Singh Varun K.
Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi, Uttar Pradesh, India
Address for correspondence: Dr. Varun K. Singh, Department of Neurology, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, Uttar Pradesh, India. E-mail: mailurvarun@gmail.com
* Contributed equally

Jul-Aug 2024
20 8 2024
27 4 441443
31 10 2023
10 6 2024
07 7 2024
Copyright: © 2024 Annals of Indian Academy of Neurology
2024
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pmcDear Editor,

Donnai–Barrow syndrome or facio-oculo-acoustico-renal syndrome (DBS/FOAR) is an autosomal recessive disorder characterised by dysmorphic facies, sensorineural hearing loss, renal and ocular abnormalities. Neurological features include intellectual disability, corpus callosum (CC) agenesis and seizures.[1] DBS is an extremely rare, inherited syndrome, with less than 50 cases reported worldwide.[2] Spastic paraparesis in DBS has not yet been described in the literature. Due to the rarity of the syndrome, all its neurological and other atypical manifestations should be reported. This will help in the early identification and rehabilitation of a person suffering from the illness, as well as in the genetic counselling of the parents. We hereby report a case of a young male presenting with spastic paraparesis that later proved to be a case of DBS by whole exome sequencing.

An 18-year-old male presented in the neurology clinic with weakness in bilateral lower limbs associated with stiffness for the last 3 months. He needed the support of one person to stand from squatting and sitting position. While walking, foot clearance was reduced on both sides. There was no weakness in the upper limbs, bowel bladder involvement or craniobulbar symptoms. He was a term baby born out of normal vaginal delivery and had a history of delayed cry at birth. There was presence of large anterior fontanelle, macrocephaly and dysmorphic facial features at birth. His developmental milestones were delayed. He was able to walk, run and climb by the age of 8 years. He was also able to eat, dress and take a bath on his own. He was diagnosed with bilateral sensorineural hearing loss (SNHL) during infancy and was prescribed hearing aids at 3 years of age. His parents started interacting with him in sign language. He was fully vaccinated as per the immunisation schedule.

When he was 6 years old, his parents noticed one of his eyes was sunken and appeared smaller. A few months later, his vision deteriorated gradually; he needed assistance in the dark, but was alright in daylight. The vision was better in the left eye, and he could watch a mobile phone or thread a needle in front of his left eye. At around 9 years of age, he was diagnosed with retinal detachment in his right eye and was operated for the same. However, his vision continued to deteriorate further. Subsequently, he was diagnosed with inoperable retinal detachment with macula involvement without any visual potential in the fellow eye. At 17 years of age, he developed colicky abdominal pain lasting for 5–6 h. It was associated with haematuria and dysuria. An evaluation revealed multiple renal cysts with cystitis, and it was treated with appropriate antibiotics. Family history revealed similar dysmorphic facial features in four siblings, three of whom died in the neonatal period due to diaphragmatic hernia and the one who is alive has retinal detachment [Figure 1].

Figure 1 Pedigree chart of the patient showing the affected siblings of the patient (black arrowhead). One elder brother is alive and has retinal detachment. His other three siblings have died.

On examination, he had dysmorphic facies like hypertelorism, prominent eyes, suborbital skin creases, flat nasal bridge, broad nasal tip, macrocephaly, right-sided microphthalmos and pectus carinatum [Figure 2a and b]. On neurological examination, he had SNHL and bilateral cataracts. There was symmetrical spastic weakness of the lower extremities (Medical research council grade 4- around both hip, knee and ankle joints). Deep tendon reflexes were normal in the upper limbs and exaggerated in the lower limbs. Plantar responses were bilateral extensors, and patellar and ankle clonus was present. There was an absence of involuntary movements like tremor, dystonia or myoclonus. Cognitive evaluation, sensory and cerebellar examination could not be done as the patient was deaf and mute. Respiratory, abdomen and cardiovascular system examination was normal.

Figure 2 Shows the presence of dysmorphic facies like hypertelorism, prominent eyes, suborbital skin creases, flat nasal bridge, broad nasal tip and right microophthalmos (a) and pectus carinatum (b) in the patient

Baseline investigations like complete haemogram, liver function test, lipid profile, thyroid profile and serum creatine kinase were normal, except hypokalaemia (serum potassium = 2.8 mEq/L) and hyperuricaemia (serum uric acid = 10.8 mg/dL). Arterial blood gas analysis was normal. Tandem mass spectrometry/gas chromatography was negative. Echocardiography was normal. Ophthalmological examination revealed bilateral retinal detachment and dense cataracts. Nerve conduction studies of all four limbs were normal. The auditory evaluation revealed bilateral moderate to severe SNHL. Computed tomography urography showed multiple Bosniak type-I cysts in the right kidney [Figure 3a]. Magnetic resonance imaging of the brain was suggestive of partial agenesis of the splenium of CC and arachnoid cyst in the retrocerebellum, while the whole spine was normal [Figure 3b]. Whole exome sequencing revealed a homozygous LRP2 novel mutation in exon 43 NM_004525.3 c. 8054delT (p. Leu2685Trpfs*119) that caused loss of normal protein function through protein truncation and frameshift mutation. A frameshift deletion ‘T’ was detected at nucleotide position 8054, which was predicted to cause loss of normal protein function through protein truncation. The frame-shifted sequence continued 119 residues until a stop codon was reached. The p.Leu2685Trpfs*119 variant was a loss-of-function variant in the gene LRP2.

Figure 3 Computed tomography urography showing multiple Bosniak type-I cysts (arrow) in the right kidney (largest measuring 1.4 × 1.9 cm) (a). MRI of the brain (sagittal view) with T1-Gd contrast sequence showing partial agenesis of the splenium of the corpus callosum and arachnoid cyst (arrows) in the cerebellum (b). MRI = magnetic resonance imaging

The above case presented with spastic paraparesis, facial dysmorphism, bilateral cataracts, retinal detachment, bilateral SNHL, renal cysts and CC agenesis. He was homozygous for a novel LRP2 frameshift deletion, which confirmed the diagnosis of DBS.

The LRP2 gene provides instructions for making a protein called megalin, which functions as a receptor. Megalin, an endocytic transmembrane receptor, is situated on the apical surface of absorptive epithelia and contains low-density lipoprotein receptor class A and B motifs, epidermal growth factor-like repeats and intracellular protein-binding Asn-Pro-X-Tyr sequences.[3] It is vital for reuptake of various ligands, including lipoproteins, sterols, vitamin-binding proteins and hormones. It has an important role in cell signalling by interacting with a sonic hedgehog.[4] Different studies in mice demonstrated the expression of megalin in specialised epithelia of various organs (brain, kidney and lung).[5]

The prevalence and incidence of DBS/FOAR is less than one per million cases.[6] At present, there are no accurate population-based incidence/prevalence data available on DBS.[2] Till now, only 49 individuals with sufficient clinical and/or molecular data to establish the diagnosis of DBS have been reported in the medical literature.[2] DBS affects people of all ethnicities, including northern and central Europeans, Middle Eastern, Americans of European origin and African Americans, and the male-to-female ratio is 1:1.[1]

Kantarci et al.[7] reported a unique DBS/FOAR patient homozygous for LRP2 deletion secondary to paternal uniparental isodisomy for chromosome 2. He had facial dysmorphic features with bilateral coloboma, agenesis of CC, gut malrotation and bilateral inguinal hernias. He had inherited the mutation from his heterozygous carrier father, whereas the mother carried only wild-type LRP2 alleles. Their case report highlighted the importance of parental genotyping for providing proper genetic counselling for autosomal recessive disorders. Sait H et al. from India described a 2-year-old male child with DBS, who presented with salt-losing tubulopathy mimicking Bartter syndrome.[8]

Differential diagnosis of DBS includes several syndromes like Lowe syndrome, Smith–Lemli–Opitz syndrome, cystinosis, Zellweger syndrome, mitochondrial disorders and Chudley–McCullough syndrome.[9]

In a systematic analysis of DBS/FOAR patients by Pober et al.,[10] the most common features were facial dysmorphism, SNHL and ocular abnormalities. Spasticity or weakness was not described in any of the reported cases. Spastic paraparesis was probably due to the corticospinal tract involvement.

The management of such patients requires a multidisciplinary approach involving a paediatrician, neurologist, ophthalmologist, otorhinolaryngologist, physiotherapist and occupational therapist and is based on the clinical manifestations present in the patient. The patients may require hearing aids and/or cochlear implants for hearing loss, corrective lenses for vision problems, cataract surgery, laser photocoagulation for retinal detachment, renal transplantation for renal failure, and surgical repair of omphalocele and diaphragmatic hernia.[21112] Schooling will help in intellectual rehabilitation management, in addition to the above.[12]

To the best of our knowledge, this is a rare case of DBS with features of spastic paraparesis. The grave clinical consequences warrant a prenatal diagnosis. Molecular diagnosis has proven to be a reliable tool for diagnosis.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient’s father has given his written and informed consent for patient’s images and other clinical information to be reported in the journal.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Acknowledgement

We acknowledge the patient for giving his consent for participating in the study.
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