Case Report

Co-existence of TBCK encephalopathy and medium/short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency (M/SCHAD) in a Puerto Rican girl

Shubhangi ChitnisORCID¹, Tamara ReynoldsORCID², Jorge VidaurreORCID³

• ¹Sacramento Service Line, Neuroscience, Pediatric Neurology, Sutter Medical Group, Sacramento, California, USA
• ²Genetics Clinic, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio, USA
• ³Division of Pediatric Neurology, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio, USA

Abstract

Keywords: TBCK; HADH; medium/short-chain 3-hydroxyacyl-CoA dehydrogenase deficiency; infantile epileptic spasms syndrome; developmental and epileptic encephalopathy; newborn screening; region of homozygosity; methylprednisolone

Case Report

We present the case of a Puerto Rican girl who was referred to our clinic for evaluation of refractory epilepsy.

She was born at 38 weeks of gestation by caesarean section due to complication of “maternal infection”. No resuscitation or interventions were needed at birth.

The family history was unremarkable. Both parents were healthy and denied consanguinity.

She presented at 8 weeks of life after a positive newborn screening test suggestive of M/SCHAD deficiency, which was confirmed by enzymatic studies. Her exam was notable for unusual facial features and severe hypotonia. At 6 months of age, she was diagnosed with infantile epileptic spasms syndrome in Puerto Rico and was treated with multiple medications, including levetiracetam, topiramate and lamotrigine, with no response. ACTH was considered but not used due to concerns about potential side effects. Finally, clobazam monotherapy resulted in a reduction of seizure frequency.

She was first evaluated at our institution at age 2 years. At that time, her seizure semiology included epileptic spasms, myoclonic, bilateral tonic-clonic, and tonic seizures.

Developmental history was significant for profound global developmental delay. She had no head control, could not sit or roll over, and did not acquire speech. There was poor weight gain, requiring gastric tube placement.

The physical exam revealed marked hypotonia, myopathic face with an inverted V-shaped mouth, and minimal movements of the face. Her eyes remained partially open while she was asleep. No dysmorphic features were noticed. Deep tendon reflexes were absent with flexor plantar responses.

She was diagnosed with hypothyroidism in Puerto Rico. However, thyroid function testing at our institution was normal after discontinuation of levothyroxine. Her cholesterol level was 493 mg/dL, triglycerides were 101 mg/dL, and LDL cholesterol was 425 mg/dL. Acylcarnitine profile demonstrated elevated C4OH consistent with a diagnosis of M/SCHAD, which was given in Puerto Rico before the patient was evaluated at our institution.

The neuroimaging was significant for diffuse white matter volume loss with periventricular gliosis, suggestive of periventricular leukomalacia/white matter insult, and enlarged ventricles (Figure 1). A cerebellar cyst was also noticed.

Long term video EEG completed at 2 years and 9 months of age showed slowing of the background activity, lack of organization and frequent multifocal, high amplitude polyspike, spike-wave discharges with temporal and occipital predominance (Figure 2).

During sleep, the background showed high amplitude delta, in addition to abundant, high amplitude generalized and multifocal spike, polyspike wave discharges creating a chaotic, disorganized pattern, consistent with hypsarrhythmia (Figure 3).

A cluster of full body myoclonus, at times associated with extension of arms (subtle epileptic spasms), were captured on video-EEG. These were associated with diffuse slow wave with frontal predominance, followed by an “electrodecremental response” (Figure 4). Electrographic seizures over the right temporal (Figure 5) and rarely left temporal (Figure 6) regions were also present.

During this hospital admission, zonisamide was added to clobazam without significant change in seizure control.

Monthly IV infusion of methylprednisolone (20 mg/kg/day for 3 consecutive days) was started. This resulted in marked seizure burden reduction and improved quality of life. Per parents' report, she became more alert and interactive, and her sleep pattern improved. No epileptic spasms were reported, but she continued to have about 2 short bilateral tonic-clonic or tonic seizures a week. Despite the positive clinical response, her background EEG remained unchanged.

She continued IV methylprednisolone infusions for about 3 years with no side effects. The infusions were discontinued without worsening seizure frequency. Stiripentol was added to clobazam. With this combination, she continued to have occasional tonic seizures and finally achieved seizure freedom.

An epilepsy panel, which consisted of sequencing and deletion/duplication analysis of 70 genes, was obtained. Two variants of uncertain significance were identified in CLN8 c.-125_-124+19dup21 and c.374A>G (p.N125S) and one variant of uncertain significance in POLG c.803G>C (p.G268A).

The CLN8 c.-125_-124+19dup21 variant has not been reported in affected patients or healthy controls. In silico prediction models predicted this variant could affect gene splicing.

The CLN8 c.374A>G (p.N125S) variant is a conservative amino acid substitution, which is not predicted to impact secondary protein structure. However, the mother was negative for both variants, confirming they were likely on the same chromosome inherited from the father. This ruled out CLN8 disease as it is autosomal recessive.

The POLG variant has been reported in individuals with both autosomal recessive and autosomal dominant progressive external ophthalmoplegia. This variant is also present in healthy controls, and in 2.4% of those with Puerto Rican ancestry. POLG was not thought to be contributory as only one variant was detected, and the child's history was not consistent with autosomal dominant POLG-related disease.

Prader-Willi/Angelman syndrome methylation analysis was normal, as was genetic testing for spinal muscular atrophy.

A single nucleotide polymorphism (SNP) microarray demonstrated a 1q21 chromosome duplication, which was also present in the mother. A single region of homozygosity (ROH) involving 10.3 Mb on 4q24-q25 was also reported. This finding raised concern for an autosomal recessive disorder caused by a gene in the area.

Whole exome sequencing (WES) identified a pathogenic homozygous nonsense variant c.376C>T (p.R126X) in the TBCK gene, and a second homozygous, likely pathogenic variant c.908G>T (p.G303V) in the HADH gene (which causes M/SCHAD). Both parents were heterozygous for each variant. Both of these genes were located in the ROH on chromosome 4 that was previously detected on SNP microarray.

All variants were classified by the testing laboratory utilizing criteria outlined in the American College of Medical Genetics interpretation guidelines [1].

Discussion

The TBCK gene encodes a GTPase activating protein (GAP). The specific function of this gene is not completely elucidated; however, recent data supports its role in cell growth and proliferation. The TBCK gene is an important gene in the regulation of the mechanistic target of rapamycin complex 1 (mTORC1) pathway [2, 3]. Autosomal recessive, loss of function TBCK mutations down regulate the mTOR pathway and have been strongly associated with severe intellectual disability [2–4].

Common phenotypes include poor psychomotor development, hypotonia, and seizures. The more affected patients are non-ambulatory, nonverbal, and manifest severe hypotonia leading to respiratory failure and gastric tube placement [3–6].

Our patient from Puerto Rican origin with a homozygous TBCK (p.R126X) variant, presented with infantile epileptic spasms syndrome and then multiple seizure types, severe hypotonia, chronic respiratory failure, profound intellectual disability and leukoencephalopathy. The same gene mutation has been described in previous case series including patients of Puerto Rican descent. These patients had a severe phenotype with age-dependent neurodegeneration and symptoms of anterior horn cell disease or distal motor neuropathy. These findings usually trigger suspicion for spinal muscular atrophy. Affected children developed early onset epilepsy, including epileptic spasms and MRI signs of leukodystrophy and brain atrophy (TBCK encephaloneuronopathy) [4]. Dyslipidaemia is itself among the systemic features reported in that cohort, alongside coarse facies and osteoporosis [4], so the marked hypercholesterolaemia in our patient may be attributable to TBCK rather than to her fatty acid oxidation defect.

Our case is unique due to the coexistence of a TBCK gene mutation along with a homozygous pathogenic variant in the HADH gene. This gene encodes the enzyme 3-hydroxyacyl-CoA dehydrogenase, which functions in the mitochondria and metabolizes preferentially medium chain as compared to short chain fatty acids (described in literature as M/SCHAD) [7–9]. Patients with M/SCHAD can present in infancy with lethargy, hypotonia, hyperinsulinism, and hypoglycaemic seizures, often in the setting of illness or fasting. Patients can remain asymptomatic, but in some cases, serious complications including liver damage, heart damage, and sudden death can occur.

The fact that these homozygous mutations were found in two separate genes located within a stretch of ROH inherited from unrelated parents of the same ancestry suggests the possibility that the variants segregate together as part of a haplotype.

This is particularly relevant for patients with Puerto Rican or Hispanic ancestry who test positive for M/SCHAD on newborn screen or are homozygous for the p.R126X variant in TBCK. The coexistence of the two conditions may lead to mistakenly attributing early symptoms to an M/SCHAD diagnosis found on newborn screen, when they may be actually the result of TBCK encephalopathy. The diagnosis of M/SCHAD may be a red herring in the early diagnostic work up before the more severe manifestations of TBCK encephalopathy appear (Table 1).

Our patient experienced a dramatic clinical response to intermittent IV methylprednisolone infusions. Soon after the initiation of steroids, parents reported resolution of epileptic spasms with reduction in frequency of bilateral tonic-clonic seizures. This finding confirms the efficacy of hormonal therapy in the treatment of epileptic spasms, independent of etiology, as demonstrated in prospective studies [10].

The early recognition of this metabolic disorder is important to initiate appropriate therapeutic interventions and prevent long-term irreversible neurodevelopmental complications [11, 12]. Addition of leucine could improve autophagic lysosomal function which has been postulated to be impaired in TBCK mutation. Leucine treatment was considered in our patient but not used. Nevertheless, her diet is closely monitored by the nutrition department. Our patient has remained stable without any metabolic crisis with current diet regimen.