Cristina Garrido

D-Bifunctional Protein Deficiency: A Cause of Neonatal Onset Seizures and Hypotonia

BACKGROUND Peroxisomal disorders are classified in two major groups: (1) peroxisome biogenesis disorders and (2) single peroxisomal enzyme/transporter deficiencies. D-bifunctional protein deficiency (OMIM #261515) is included in this last group of rare diseases and leads to an impaired peroxisomal beta-oxidation. D-bifunctional protein deficiencies are divided into four types based on the degree of activity of the 2-enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase protein units. PATIENT DESCRIPTION We present the first Portuguese reported type II D-bifunctional protein deficiency patient, whose neonatal clinical picture is indistinguishable from a Zellweger spectrum disease. The clinical features and the neuroimaging findings of polymicrogyria raised suspicion of the diagnosis. After biochemical analysis, D-bifunctional protein deficiency was confirmed with the identification of a homozygous p.Asn457Tyr (N457Y) mutation of the HSD17B4 gene. The patients parents were carriers of the mutated allele, confirming the patient homozygosity status and allowing prenatal diagnosis in future pregnancies. CONCLUSIONS D-bifunctional protein deficiency is a rare, severe disease and the final diagnosis can only be accomplished after HSD17B4 gene sequencing. Treatment is supportive, aimed at improving nutrition and growth, controlling the central nervous system symptoms, and limiting the eventual progression of liver disease.

Refractory epilepsy in Norrie disease

Dear Professor Federico, Norrie disease is a NDP-related retinopathy characterized by congenital blindness with progressive loss of hearing and neurological features first reported by Gordon Norrie in 1927 [1]. Its gene mutation has been recently described and helped to define a large spectrum of phenotypic manifestations. The diagnosis relies on a combination of clinical findings and molecular genetic testing, which identifies pathogenic variants in approximately 95% of affected males [1–3]. Norrie disease is an X-linked recessive disorder resulting from a disruption of the NDP gene (Xp11.4) [2], which encodes the protein norrin. This is a secreted protein with a cysteine-knot motif that acts as a ligand in the WNT receptor-b-catenin signal transduction pathway, which is thought to regulate retinal angiogenesis and to be required for regression of hyaloid vessels in the eye [2]. In the inner ear, it is thought to regulate vascular maintenance since hearing is normal in early childhood [2]. NDP-related retinopathies cause varying degrees of visual impairment characterized by a spectrum of fibrous and vascular changes of the retina at birth that progress through childhood or adolescence [1]. The ocular phenotype in Norrie disease is typically characterized by grayish yellow fibrovascular masses (pseudogliomas) secondary to retinal vascular dysgenesis and detachment [1, 2]. Although phenotypes vary even within families, the majority of males with Norrie disease also develop sensorineural hearing loss and approximately 30–50% have cognitive impairment with learning disabilities, behavioral abnormalities, or psychotic-like features [1]. Epilepsy is an uncommon manifestation of this rare disease, reported in less than 10% of the cases [2] and usually controlled with antiepileptic drugs. We report a patient with Norrie disease associated to refractory epilepsy. We present a 17-year-old boy with amaurosis secondary to bilateral congenital retinal dysplasia diagnosed in the first months of life. He started having generalized tonic-clonic seizures since he was 6 years old. One year later, he developed a febrile convulsive status epilepticus. His first electroencephalogram (EEG) presented right frontotemporal spikes and sharp waves. Brain magnetic resonance imaging was unremarkable. Psychomotor development and auditory potentials were normal. Initially, he was treated with sodium valproate, which was withdrawn due to toxic hepatitis, and then he was started on phenobarbitone 5 mg/ kg/day being seizure free until the age of 10 years, when he started presenting atonic seizures. Carbamazepine 800 mg/day was added with reduction on seizure frequency. At the age of 14, he started having daily seizures characterized by a 2to 3-s stretching of both arms and, less often, paresthesia’s followed by clonic movements of the left arm, some evolving to bilateral tonic-clonic seizures. Multiple EEGs showed a base rhythm disorganization and multifocal spikes, spike waves, and sharp waves, with different focalization and lateralization, being sometimes generalized (Fig. 1). Levetiracetam 3000 mg/day and clonazepam 6 mg/day were started and phenobarbitone was withdrawn. Due to lack of control, zonisamide 500 mg/day was added and later, phenytoin 300 mg/day, lamotrigine 400 mg/day, and clobazam 10 mg/day were tried. Regardless of different antiepileptic drug (AED) combinations, seizures were never controlled. Nowadays, he is on four AED (rufinamide 800 mg/day, zonisamide 500 mg/day, lamotrigine 400 mg/day, and clobazam 10mg/day) and presents weekly seizures of different types, mostly tonic, spasms, and focal with behavior arrest. His last EEG showed base rhythm disorganization with left frontal spikes and he is now proposed to vagus nerve stimulation. * Gonçalo Cação goncalo.cacao@gmail.com