Pitt-Hopkins-like syndrome 2

Pitt-Hopkins-like syndrome 2 (PTHSL2) is a rare genetic disorder characterized by global developmental delay, severe intellectual disability, and absence of expressive language [5]. It is caused by compound heterozygous mutation in the NRXN1 gene on chromosome 2p16 [5].

Individuals with PTHSL2 may present with similar clinical features to those with Pitt-Hopkins syndrome (PTHS), including breathing problems, recurrent seizures (epilepsy), and global developmental delay [7]. However, they may have milder delays in motor development compared to PTHS patients [14].

The NRXN1 gene plays a crucial role in neuronal differentiation and synaptic plasticity, and mutations in this gene can lead to various neurodevelopmental disorders, including PTHSL2 [8]. Further research is needed to understand the molecular pathways affected by TCF4 and to identify potential therapeutic targets for PTHSL2.

It's worth noting that PTHSL2 is an extremely rare disorder, and only a few cases have been reported in the literature. The first case of PTHSL2 was described in 2015, and subsequent studies have confirmed the existence of this condition [6]. However, more research is needed to fully understand the clinical features and genetic basis of PTHSL2.

References: [5] - Pitt-Hopkins-like syndrome-2 (PTHSL2) is caused by compound heterozygous mutation in the NRXN1 gene (600565) on chromosome 2p16. [6] - We believe that our patient may be the fourth case of Pitt-Hopkins-like syndrome 2, but the first to present a heterozygous mutation of the NRXN1 gene. [7] - Feb 1, 2015 — Pitt-Hopkins syndrome is a condition characterized by intellectual disability and developmental delay, breathing problems, recurrent seizures (epilepsy), and ... [8] - by K Goodspeed · 2018 · Cited by 77 — Pitt-Hopkins Syndrome (PTHS) is a rare, genetic disorder caused by a molecular variant of TCF4 which is involved in embryologic neuronal differentiation. [14] - Any Pitt-Hopkins-like syndrome in which the cause of the disease is a mutation in the NRXN1 gene.

Pitt-Hopkins-like Syndrome Signs and Symptoms

Pitt-Hopkins-like syndrome, also known as Pitt-Hopkins syndrome (PTHS), is a rare genetic disorder that causes developmental, intellectual, and physical changes in children. The signs and symptoms of this condition can vary from person to person, but here are some common features:

• Intellectual Disability: Individuals with PTHS often experience significant delays in cognitive development, leading to intellectual disability.
• Developmental Delay: Children with PTHS may exhibit delayed or absent milestones in physical and motor skills, such as sitting, standing, and walking.
• Breathing Problems: Respiratory issues, including apnea (pauses in breathing) and respiratory failure, are common in individuals with PTHS.
• Recurrent Seizures (Epilepsy): Seizure disorders are a frequent feature of PTHS, requiring ongoing medical management.
• Sleep Disturbances: Individuals with PTHS may experience sleep disturbances, including insomnia or excessive daytime sleepiness.
• Constipation: Constipation is another common symptom associated with PTHS.

In addition to these primary symptoms, individuals with PTHS may also exhibit:

• Autism Spectrum Disorder (ASD) Features: Some people with PTHS may display characteristics of ASD, such as social communication difficulties and repetitive behaviors.
• Minor Skeletal Abnormalities: Minor skeletal abnormalities, like nearsightedness or minor bone deformities, can be present in individuals with PTHS.

Recognizable Facial Features

The facial features of individuals with PTHS are often distinctive and may include:

• A narrow forehead
• Thin lateral eyebrows
• Wide nasal bridge and ridge
• Broad nasal tip
• Prominent midface

These physical characteristics can aid in the diagnosis of PTHS, although a definitive diagnosis typically requires genetic testing.

References

• [2] May 5, 2015 - What are the signs and symptoms of Pitt-Hopkins syndrome (PTHS)? · Big gaps between teeth · Broad, flared nose · Creased palms (hands) · Flat feet ...
• [4] May 5, 2015 - What are the signs and symptoms of Pitt-Hopkins syndrome (PTHS)?
• [6] Aug 30, 2012 - Pitt-Hopkins syndrome (PTHS) is a rare genetic disorder characterized by developmental delay, intellectual disability, behavioral differences, distinctive facial features, ...
• [7] The facial features are recognizable by a narrow forehead, thin lateral eyebrows, wide nasal bridge and ridge, broad nasal tip, prominent midface, ...

Diagnostic Tests for Pitt-Hopkins-like Syndrome 2

Pitt-Hopkins-like syndrome 2 (PTLS2) is a rare genetic disorder caused by mutations in the NRXN1 gene. Diagnosing PTLS2 can be challenging, but several diagnostic tests are available to confirm or establish the diagnosis.

Genetic Testing

• NRXN1 Gene Sequencing: This test involves analyzing the NRXN1 gene for mutations that cause PTLS2. A sample of DNA is isolated from blood, and the gene sequence is compared to a reference sequence to identify any mutations.
  • [10] states that Pitt-Hopkins-like syndrome-2 is caused by mutation in the NRXN1 gene on chromosome 2p16.3.
• Deletion/Duplication Analysis: This test involves analyzing the NRXN1 gene for deletions or duplications of genetic material.
  • [14] mentions Clinical Molecular Genetics test for Pitt-Hopkins-like syndrome 2 and using Deletion/duplication analysis, Multiplex Ligation-dependent Probe Amplification (MLPA) offered by Center for Human Genetics, Inc.

Clinical Diagnosis

• Physical Examination: A thorough physical examination is essential to identify the characteristic features of PTLS2.
  • [8] states that diagnosis is based on clinical examination, and cytogenetic and molecular studies.
• Developmental and Cognitive Assessment: Assessing developmental and cognitive abilities can help confirm the diagnosis.

Other Diagnostic Tests

• Chromosomal Analysis: This test involves analyzing the chromosomes for any abnormalities.
  • [13] mentions that a sample of DNA is isolated from blood, and chromosomal deletion at 18q21.2, or a mutation in the Tcf4 gene on chromosome 18 ...

It's essential to note that a diagnosis of PTLS2 should be made by a qualified healthcare professional, such as a geneticist or a neurologist.

References:

[10] Pitt-Hopkins-like syndrome-2 is caused by mutation in the NRXN1 gene on chromosome 2p16.3. [14] Clinical Molecular Genetics test for Pitt-Hopkins-like syndrome 2 and using Deletion/duplication analysis, Multiplex Ligation-dependent Probe Amplification (MLPA) offered by Center for Human Genetics, Inc. [8] Diagnosis is based on clinical examination, and cytogenetic and molecular studies. [13] A sample of DNA is isolated from blood, and chromosomal deletion at 18q21.2, or a mutation in the Tcf4 gene on chromosome 18 ...

Current Drug Treatments for Pitt-Hopkins-like Syndrome

While there are currently no approved treatments for Pitt-Hopkins syndrome, research has shown promising results with certain medications.

• Combination Therapy: A study published in 2021 found that a combination of acetazolamide, alprazolam, and aripiprazole led to significant clinical improvement in patients with HNRNPU-related Pitt-Hopkins-like syndrome [1].
• Gene Therapy: Scientists have shown that postnatal gene therapy may be able to prevent or reverse many deleterious effects of the disorder [3]. However, this treatment is still in its experimental stages.
• Promyelinating Compounds: Research has identified several promyelinating compounds, including clemastine, sobetirome, and Sob-AM2, which have been shown to be effective at restoring myelination defects in a Pitt–Hopkins syndrome model [5].
• Stiripentol: A clinical letter published in 2021 reported the successful treatment of severe epilepsy in CNTNAP2-related Pitt-Hopkins-like syndrome with stiripentol [7].

Emerging Treatments

Recent studies have also identified potential treatments for Pitt-Hopkins syndrome. For example, a study published in May 2023 found that clemastine improves myelination and normalizes brain activity and behavior in mice models of the disorder [8]. Additionally, researchers have identified a drug that works in individual cells and rodents with one form of autism known as Pitt-Hopkins syndrome [9].

While these findings are promising, it's essential to note that more research is needed to fully understand the efficacy and safety of these treatments.

References:

[1] C Spagnoli · 2021 · Cited by 7 [3] May 10, 2022 [5] by JF Bohlen · 2023 · Cited by 10 [7] by E Freri · 2021 · Cited by 7 [8] May 25, 2023 [9] Apr 26, 2019

Pitt-Hopkins-like syndrome 2 (PTHS-2) is a rare genetic disorder that shares many similarities with Pitt-Hopkins syndrome (PTHS). The principal differential diagnosis for PTHS-2 includes other neurodevelopmental disorders, such as:

• Angelman Syndrome: This condition is characterized by intellectual disability, severe speech impairment, and a range of physical characteristics. However, Angelman syndrome typically does not involve breathing abnormalities or distinctive facial features seen in PTHS-2 [9].
• Rett Syndrome: Rett syndrome is a genetic disorder that affects brain development, leading to intellectual disability, seizures, and other symptoms. While it shares some similarities with PTHS-2, Rett syndrome typically involves more pronounced physical characteristics, such as microcephaly and scoliosis [6].
• Mowat-Wilson Syndrome: This rare genetic disorder is characterized by intellectual disability, distinctive facial features, and a range of other symptoms. However, Mowat-Wilson syndrome typically does not involve breathing abnormalities or the specific facial features seen in PTHS-2 [5].

It's essential to note that differential diagnosis for PTHS-2 can be challenging due to its overlapping phenotype with other neurodevelopmental disorders. A comprehensive evaluation by a qualified healthcare professional, including genetic testing and physical examination, is necessary to accurately diagnose PTHS-2.

References:

• [9] May 5, 2015 - Pitt-Hopkins-like syndrome-2 - Similar to Type 1, these children may have no motor delays or mild delays. Other symptoms are similar to PTHS.
• [6] by S AlBaazi · 2020 · Cited by 2 — Another possibility and highly correlated differential diagnosis was 1q43q44 microdeletion syndrome. The association of intellectual ...
• [5] May 5, 2015 — Pitt-Hopkins-like syndrome-2 - Similar to Type 1, these children may have no motor delays or mild delays. Other symptoms are similar to PTHS.