Pitt-Hopkins-Like Syndrome 1

A number sign (#) is used with this entry because of evidence that Pitt-Hopkins-like syndrome-1 (PTHSL1) is caused by homozygous or compound heterozygous mutation in the CNTNAP2 gene (604569) on chromosome 7q35-q36.

Description

PTHSL1 is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, severe speech impairment or regression, and behavioral abnormalities. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging (summary by Smogavec et al., 2016).

Clinical Features

Strauss et al. (2006) described a clinical and neuropathologic phenotype, which they called cortical dysplasia-focal epilepsy syndrome (CDFES), in 9 children in the Old Order Amish of Lancaster, Pennsylvania. During infancy, all patients had mild gross motor delay and subtle limitations in motor skills. Eight of 9 children had good language comprehension and general development by age 18 months. There were no distinguishing physical features, and growth trajectories were normal, although all patients had relatively large heads and diminished or absent deep-tendon reflexes. Severe intractable seizures began between 2 and 7 years of age and were associated with deterioration of learning ability and social behavior. Those older than 3 years had language regression, aberrant social interactions, and mental retardation, and showed hyperactivity, inattention, and aggression. Brain MRI showed focal malformations in 3 of 7 patients studied: 2 had unilateral dysplasia of the anterior temporal lobe and 1 had a malformation of the left striatum. Resective surgery did not prevent the recurrence of seizures. The long-term outcome was poor, with patients fully dependent on others for daily living.

Pitt-Hopkins-Like Syndrome 1

Orrico et al. (2001) described 2 sibs, a brother and sister, with severe mental retardation and multiple congenital anomalies including coarse facial features, short stature, seizures, hypertrichosis, short great toes, and overbreathing. The authors stated that comparison of these patients with previous reports suggested that they could represent the first familial cases of Pitt-Hopkins syndrome (PTHS; 610954). Peippo et al. (2006) noted that the clinical features of the sibs described by Orrico et al. (2001) differed in several respects from those of other PTHS patients described in the literature. The noses were merely large as opposed to beaked with flared nostrils; upper lips lacked the typical curving; both sibs had unilateral ptosis not found in other patients; and motor development was normal. Breathing abnormality also differed, with loss of consciousness in the elder sib during apnea, and breathing irregularity without apnea in the younger sib. In a follow-up of the 2 sibs reported by Orrico et al. (2001), Zweier et al. (2009) stated that the patients had normal growth apart from short stature, lack of speech development, and no specific facial dysmorphism aside from thick lips and wide mouth. Seizure onset was around 2 years of age, and 1 patient had cerebellar hypoplasia. Autistic features were not noted.

Zweier et al. (2009) also reported an 11-year-old girl with normal growth, severe mental retardation, lack of speech development, and onset of seizures at 4 to 8 months of age. She had hyperbreathing and showed stereotypic behaviors, such as teeth grinding, as well as autistic behavior. She was considered normal until age 8 months and thereafter showed developmental regression. Brain MRI results were not known. Zweier et al. (2009) noted that this patient had a similar phenotype to that reported by Orrico et al. (2001).

Smogavec et al. (2016) reported 8 patients from 6 unrelated families with moderate to severe intellectual disability with speech impairment, behavioral abnormalities, and early-onset seizures. The patients were ascertained from different genetics or pediatric neurology centers worldwide, and ranged from 2 to 47 years of age. Most had very poor or absent speech with few words and poor verbal comprehension, and several patients had loss of verbal skills or stagnation of language development. The patients had delayed walking between 18 and 5 years; 1 patient was nonambulatory at age 14. Seizure types included complex focal, focal tonic, temporal, and generalized, with EEG showing focal seizures as well as generalized slowing. Most patients had a favorable response to antiepileptic medication. Brain imaging showed suspected temporal cortical dysplasia in 2 patients and vermian atrophy in another, but MRI was normal in 3. Other variable neurologic abnormalities included hyporeflexia, hypotonia, ataxia, and spasticity. Behavioral anomalies included stereotypic hand movements, aggressivity, autoaggressivity, and reduced eye contact. One patient had hyperventilation. There were no significant or common facial dysmorphic features. Of note, 2 adult brothers had variable severity: 1 had severe intellectual disability and was nonverbal at age 47, whereas the other had moderate intellectual disability with basic literacy skills and could speak at age 40.

Inheritance

The transmission pattern of PTHSL1 in the families reported by Smogavec et al. (2016) was consistent with autosomal recessive inheritance.

Mapping

Strauss et al. (2006) mapped the CDFE syndrome to 7q36 by demonstration of a large block of putative autozygosity.

Molecular Genetics

Strauss et al. (2006) found a homozygous 1-bp deletion in the CNTNAP2 gene (3709delG; 604569.0001) in 13 patients with CDFES from 10 sibships.

Zweier et al. (2009) identified homozygous or compound heterozygous mutations in the CNTNAP2 gene (604569.0005-604569.0007) in 2 sibs and 1 unrelated child with mental retardation, early seizure onset, and hyperbreathing patterns. The phenotype overlapped that of Pitt-Hopkins syndrome and is designated here as Pitt-Hopkins-like syndrome-1. Studies in Drosophila suggested a role for the CNTNAP2 protein at the synapse.

In 8 patients from 6 unrelated families with PTHSL1, Smogavec et al. (2016) identified homozygous or compound heterozygous truncating mutations and/or intragenic deletions in the CNTNAP2 gene (see, e.g., 604569.0008-604569.0013). The patients were ascertained from different genetics or pediatric centers worldwide. The mutations and deletions were found by various methods, including microarray analysis, gene panel sequencing, and targeted sequencing. Carrier parents were unaffected, although 1 had anxiety and emotional lability; none underwent psychiatric testing. Functional studies of the variants were not performed, but all were predicted to result in a loss of function.