Tsen54 Pontocerebellar Hypoplasia

Clinical characteristics.

TSEN54 pontocerebellar hypoplasia (TSEN54-PCH) comprises three PCH phenotypes (PCH2, 4, and 5) that share characteristic neuroradiologic and neurologic findings. The three PCH phenotypes (which differ mainly in life expectancy) were considered to be distinct entities before their molecular basis was known.

• PCH2. Children usually succumb before age ten years (those with PCH4 and 5 usually succumb as neonates). Children with PCH2 have generalized clonus, uncoordinated sucking and swallowing, impaired cognitive development, lack of voluntary motor development, cortical blindness, and an increased risk for rhabdomyolysis during severe infections. Epilepsy is present in approximately 50%.
• PCH4. Neonates often have seizures, multiple joint contractures ("arthrogryposis"), generalized clonus, and central respiratory impairment.
• PCH5 resembles PCH4 and has been described in one family.

Diagnosis/testing.

The diagnosis of TSEN54-PCH is suspected in children with characteristic neuroradiologic and neurologic findings, and is confirmed by the presence of biallelic TSEN54 pathogenic variants.

Management.

Treatment of manifestations: PCH2: Treatment of irritability, swallowing incoordination, epilepsy, and central visual impairment is symptomatic. Physiotherapy can be helpful. Adequate hydration during prolonged periods of high fever may help avoid rhabdomyolysis. PCH4 and PCH5: No specific therapy is available.

Surveillance: PCH2: Routine monitoring of respiratory function, feeding, musculoskeletal and neurologic manifestations, developmental milestones, and family needs.

Genetic counseling.

TSEN54-PCH is inherited in an autosomal recessive manner. If each parent is known to be heterozygous for a TSEN54 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of inheriting one pathogenic variant and being an unaffected carrier, and a 25% chance of inheriting both normal alleles. Once the TSEN54 pathogenic variants have been identified in an affected family member, molecular genetic testing to determine carrier status of at-risk relatives, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible.

Suggestive Findings

TSEN54-PCH should be suspected in children with severe neurologic impairment and the following findings on brain imaging [Barth et al 2007, Steinlin et al 2007, Namavar et al 2011].

Brain MRI Findings

Common findings

• Cerebellar hypoplasia and varying degrees of cerebellar atrophy (more severe in PCH4).
• Ventral pontine atrophy, present in the majority of cases (more severe in PCH4).
• Cerebellar hemispheres more affected than cerebellar vermis
• Cerebral cortical atrophy, progressive with age
• Pericerebral CSF accumulation and delayed neocortical maturation in PCH4

Less common findings (not present in all persons) (see Figure 1)

Figure 1.

MRI of the brain of an infant age two months with PCH2 a. Midsagittal image showing hypoplastic vermis and flat ventral pons (arrow)

• Striatal hypoplasia or atrophy
• Delayed myelination of the brain in the first years; no demyelination; gliosis in PCH4
• Exceptional: cerebellar hemispheric cysts in PCH2

Family history consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

Diagnosis of TSEN54-PCH is established in a proband with suggestive findings and biallelic TSEN54 pathogenic variants identified by molecular genetic testing (see Table 1).

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing or multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive brain imaging findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of TSEN54-PCH has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

To date, at least 131 individuals have been identified with TSEN54 pontocerebellar hypoplasia (TSEN54-PCH) [Namavar et al 2011, Sánchez-Albisua et al 2014].

The phenotypic spectrum of TSEN54-PCH comprises the three PCH phenotypes (PCH 2, 4, and 5) thought to be distinct entities before their molecular basis was known. The main difference between the three PCH phenotypes is life expectancy: individuals with PCH2 usually survive into childhood, whereas those with PCH4 and PCH5 usually die as neonates.

Genotype-Phenotype Correlations

The following clinical data, supported by pathogenic data, strongly suggest a genotype-phenotype correlation.

The common c.919G>T missense variant is strongly associated with a dragonfly-like cerebellar pattern on MRI.

In general, infants with the PCH4 phenotype who are compound heterozygotes for a pathogenic nonsense or splice site variant and a pathogenic missense variant have poorer survival than children with the PCH2 phenotype who are homozygous for a missense variant [Budde et al 2008, Namavar et al 2011].

Nomenclature

Pontocerebellar hypoplasia 2 (PCH2) refers to the phenotype; its subtypes are identified by the gene in which causative variants occur:

• PCH2A (TSEN54)
• PCH2B (TSEN2)
• PCH2C (TSEN34)
• PCH2D (SEPSECS)

Prevalence

The prevalence of TSEN54-PCH is unknown. To date, at least 131 individuals have been identified with TSEN54-PCH.

The carrier frequency of the common TSEN54 pathogenic variant c.919G>T (p.Ala307Ser) among 451 Dutch and 279 German individuals was 0.004 [Budde et al 2008].

Like many autosomal recessive disorders, PCH2 has been reported to be more common in isolated populations or populations with a high rate of consanguinity. PCH2 was originally identified in an isolated population in Volendam, the Netherlands [Barth et al 1995].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with TSEN54 pontocerebellar hypoplasia (TSEN54-PCH), the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to the diagnosis) are recommended. Note that recommendations are based only on PCH2 caused by homozygosity for theTSEN54 pathogenic variant c.919G>T, as all other subtypes are very rare.

Treatment of Manifestations

PCH4 and PCH5. No specific therapy is available. Respiratory support is usually given for a limited time. Weaning from respiratory support may be possible for only short periods.

PCH2. Although there is no specific treatment, the goals are to maximize function and reduce complications. Ideally each affected individual is managed by a multidisciplinary team of relevant specialists such as developmental pediatricians, neurologists, occupational therapists (OT), physical therapists (PT), physiatrists, orthopedists, nutritionists, pulmonologists, and psychologists depending on the clinical manifestations (see Table 5).

Of note, adequate hydration during prolonged periods of high fever may help avoid rhabdomyolysis.