Intractable epileptic spasms in a patient with Pontocerebellar hypoplasia: Severe phenotype of type 2 or another subtype?

INTRODUCTION: Pontocerebellar hypoplasia (PCH) involves a diverse range of etiologies including a group of single gene disorders. Mutations in the tRNA splicing endonuclease complex (TSEN) 54 gene can be responsible for PCH type 2, 4 and 5. The more common and less severe PCH 2 phenotype is caused by homozygosity for the common missense mutation A307S, while the severe phenotype seen in type 4 and 5 is caused by compound heterozygosity of the A307S mutation along with a nonsense or splice site mutation. REPORT: We report a 4- month-old girl who presented with epileptic spasms that remained intractable to several antiepileptic medications. Magnetic Resonance Imaging (MRI) brain showed fairly severe hypoplasia with superimposed atrophy of the cerebellum and brainstem with prominent extra-axial fluid spaces. Extensive metabolic testing was negative. Commercial testing for PCH via TSEN54 gene revealed missense mutation of Ala307Ser. A novel sequence variant, designated c.17_40 del, was also found and was predictive of an in-frame deletion of eight amino acids. Follow-up over 2 years revealed intractable epileptic spasms, progressive microcephaly and development of prominent choreoathetosis.
CONCLUSION: This case report describes a rare case of PCH with overlapping features of the less severe PCH2 and the more severe PCH4/5 phenotype. It also adds another new entity in the list of genetic conditions where West syndrome and pontocerebellar hypoplasia can be seen together, emphasizing the need for further investigations of the genotype-phenotype correlation of mutations in order to advance our understanding of the pathophysiologic mechanism in these rare conditions.

Introduction

A group of single gene disorders, among diverse range of etiologies, can cause pontocerebellar hypoplasia (PCH).[1] There are several subtypes of PCH, and the correct molecular identification of the type is important for counseling and prognostication. One particular gene- TSEN (tRNA splicing endonuclease complex) 54 mutation- can be responsible for PCH type 2, 4, and 5. The more common PCH 2 phenotype is caused by homozygosity for the common missense mutation -A307S and manifests with less severe phenotype. On the contrary, severe phenotype seen in type 4 and 5 is caused by compound heterozygosity of the A307S mutation along with additional nonsense or splice site mutation of TSEN54 gene. We report a confirmed case of TSEN54 mutation associated PCH who presented with epileptic spasms and has overlapping features of multiple subtypes of PCH.

Case Report

A 4-month-old girl presented with complaints of seizure-like activity. She was born to a 20-year-old primigravida mother via spontaneous vaginal delivery at 34 weeks gestation with a birth weight of 5 pounds 14 ounces. Maternal history was significant for preeclampsia and cholestasis in the last trimester of pregnancy. The patient had an extended course in the neonatal intensive care unit (ICU) for feeding difficulties with eventual gastrostomy tube placement. She had an electroencephalography (EEG) performed at 2 weeks of age due to episodes of desaturation which revealed no electrographic seizures, but background was excessively discontinuous for the gestational age. MRI brain showed fairly severe hypoplasia with superimposed atrophy of the cerebellum and brainstem as well as prominent extra-axial fluid spaces [Figure 1]. At presentation, she was noted to have microcephaly, lack of visual tracking, and bilateral esotropia. Her tone was increased in both upper and lower extremities with brisk tendon reflexes and bilateral ankle clonus. Babinski sign was positive bilaterally. Video EEG captured several episodes of epileptic spasms which remained intractable to levetiracetam, topiramate, and vigabatrin. Ketogenic diet provided short-term improvement, but seizure frequency returned to the previous frequency in spite of consistent urine ketone level of 40–80 mg/dl. Interictally, her background activity was diffusely slow with multifocal spike and wave discharges [Figure 2]. Parents declined adrenocorticotropic hormone (ACTH) and steroid therapy. Extensive metabolic testing such as renal panel with electrolytes, glucose, liver panel, serum electrolytes, urinalysis, serum lactate and pyruvate, plasma ammonia, urine organic acids, serum and urine organic acids was normal. Cerebro-spinal fluid (CSF) study of cell count, chemistry, lactate, pyruvate, amino acids and neurotransmitters was also normal. Chromosomal microarray did not reveal a diagnosis. Commercial testing for PCH via TSEN54 gene sequencing revealed sequence variant designated c.919G > T, which is predicted to result in amino acid substitution p. Ala307Ser. A novel sequence variant, designated c.17_40 del, predictive of in-frame deletion of eight amino acids, was also found. Follow-up over 2 years revealed intractable epileptic spasms, progressive microcephaly and development of prominent choreoathetosis. She didn’t attain head control, social smile or ability to visually track. She had frequent admissions in the ICU due to breathing difficulties. The three-generation pedigree didn’t reveal any family members with similar illness, but genetic counselling was provided to the parents as TSEN54-related PCH is inherited in an autosomal recessive manner.

Figure 1

(a) Mid-sagittal section (T1) shows hypoplasia with superimposed atrophy of the vermis and brainstem. (b) Axial section shows increased pericerebral cerebrospinal fluid accumulation between the cortical surface and the skull, mild cerebral atrophy, and delayed neocortical maturation. (c) Coronal image shows cerebellar hemispheres more affected than cerebellar vermis to give a dragon-fly like cerebellar pattern

Figure 2

Background shows diffuse high amplitude slowing with multifocal and generalized spike wave discharges

Discussion

PCHs are a group of clinically and genetically heterogeneous disorders characterized by Cerebellar hypoplasia, varying degrees of cerebellar atrophy, and Ventral pontine atrophy.[2] Seven subtypes have been described.[3] Among these, PCH types 2, 4 and 5 are caused by mutations in the TSEN54 gene. All these subtypes have absence of transverse pontine fibers and atrophy of the cerebellar folia, but PCH 4 and 5 have a more severe clinical course, with significant hypertonia and early neonatal death.

PCH2 is characterized by seizure, developmental delay, hyperkinetic movements, visual defects, hypotonia and weakness. Seizures occur in more than 80% of these patients with mean age of onset at 2 year 5 months. Many different seizure types have been described such as febrile seizures, tonic-clonic, atypical absence, myoclonic, tonic, focal, and atonic seizures.[34] Seizures are usually intractable to anti-epileptic drugs, and a significant proportion of these patients can develop status epilepticus. Unremarkable EEG during neonatal age group changes to abnormal with growing age with evident diffuse slowing and multifocal epileptiform discharges. Typical brain MRI findings include a dragonfly-like cerebellar pattern on coronal sections as the cerebellar hemispheres are severely reduced in size though the vermis remains relatively spared.

TSEN gene encodes tRNA splicing endonuclease complex which catalyzes the removal of introns from precursor tRNAs to form mature tRNAs; it is essential for translation of messenger RNA (mRNA) into proteins.[5] This enzyme complex may be also necessary for polyadenylation of mRNA. Mutations in the TSEN54 gene (located on the long arm of chromosome 17) disrupts the processing of RNA molecules and present for over 90% of patients with PCH2. Homozygous missense mutation of A307S replaces the amino acid alanine with the amino acid serine at position 307 in the TSEN54 and is responsible for the vast majority of TSEN54 mutations in PCH2. However, compound heterozygosity for nonsense or a splice site mutation along with the missense mutation in TSEN54 is seen in both PCH4 and PCH5. These subtypes are associated with increased severity of hypoplasia of the pons and cerebellum and immaturity of the cerebral cortex with more perinatal symptoms and earlier lethality than seen in PCH2. PCH type 4 is characterized by severe perinatal symptoms such as excessive clonus, congenital contractures, polyhydramnios and primary hypoventilation necessitating prolonged mechanical ventilation. Survival through the neonatal period and weaning from ventilation are extremely rare event. Pericerebral CSF accumulation, wide midline cava and delayed neocortical maturation are distinctive feature of this subtype. Only arbitrary difference exists between PCH4 and PCH5.[6] In PCH5 the vermis is more affected than the hemispheres whereas in PCH4 the vermis and the hemispheres are both severely affected. Though, PCH4 and PCH5 are phenotypically more severe than PCH2, cases with overlapping features can exist and genotypic data may help with prognostication. Complementary genetic information with consistent clinical and neuroimaging finding may not only help with prognostication related to survival, but also provide guidance regarding treatment such as preventive strategies for sleep apnea, fever induced seizures, and anesthetic induced malignant hyperthermia. Some other single gene disorders such as RELN, CHMP1A and CASK can have similar clinical and neuroimaging finding with PCH TSEN 54 and availability of genetic data can modify the counselling as inheritance pattern may be different, for example, X-linked inheritance seen with mutation of CASK gene.

In our patient, missense mutation with amino acid substitution p. Ala307Ser was seen along with a novel sequence variant designated c.17_40 del, predictive of in-frame deletion of eight amino acids. This additional mutation made the phenotype much more severe with neonatal onset severe feeding difficulty and early onset intractable epileptic spasms. Epileptic spasm has not been published in the literature with this genotype to the best of our knowledge. MRI imaging also showed some features of PCH 4 or 5 with pericerebral CSF accumulation and presence of midline cava. However, her feature is much less severe compared to a classic case of PCH 4 or PCH 5. She is still alive at 2.5 years with no ventilator- dependence.

Several genetic based conditions are associated with early onset epileptic encephalopathy and epileptic spasms. Disruption of translation of protein, due to TSEN mutation, makes developing neuronal tissue sensitive to significant desynchronization — prominent feature of epileptic spasm. Several other genetic conditions can present with pontocerebellar hypoplasia and West syndrome such as congenital disorders of glycosylation, progressive cerebello-cerebral atrophy (missense mutations in SEPSECS), and infantile cerebral and cerebellar atrophy (missense mutations in MED17). This report adds another new entity in that list. This description also highlights the overlapping features of different PCHs. Further investigation of the genotype-phenotype correlation of mutations may contribute to our understanding of pathophysiologic mechanism in these rare conditions.