neurodevelopmental disorder with midbrain and hindbrain malformations

Neurodevelopmental Disorder with Midbrain and Hindbrain Malformations (NEDMHM)

NEDMHM is a rare genetic disorder characterized by malformations in the midbrain and hindbrain, leading to various neurological and developmental abnormalities. The condition is inherited in an autosomal recessive pattern, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the disorder.

Key Features:

• Intellectual Disability: Individuals with NEDMHM often experience intellectual disability, ranging from mild to severe [1][2].
• Midbrain and Hindbrain Malformations: The condition is characterized by malformations in the midbrain and hindbrain, which can lead to various neurological symptoms [3][4].
• Microcephaly: Mild microcephaly (small head size) is a common feature of NEDMHM [5][6].
• Decreased Reflexes: Individuals with NEDMHM may experience decreased reflexes and impaired fine motor movements [7][8].

Causes and Inheritance

NEDMHM is caused by mutations in genes that are essential for the development of the midbrain and hindbrain. The condition is inherited in an autosomal recessive pattern, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the disorder [9].

References:

[1] Context 1 [2] Context 6 [3] Context 7 [4] Context 8 [5] Context 10 [6] Context 5 [7] Context 3 [8] Context 10 [9] Context 9

Common Signs and Symptoms

Individuals with neurodevelopmental disorders involving midbrain and hindbrain malformations may exhibit a range of signs and symptoms, including:

• Hypotonia: Weakness or low muscle tone [7]
• Motor retardation: Delayed motor development [7]
• Ataxia: Difficulty with coordination and balance [7, 9]
• Variable degree of intellectual disability: Ranging from mild to severe cognitive impairment [7, 9]
• Abnormal eye movements: Nystagmus or other unusual eye movements [2, 5, 6]

Additional Symptoms

Some individuals may also experience:

• Feeding problems: Difficulty with feeding and swallowing [10]
• Early hyperreflexia: Increased reflexes in early childhood [10]
• Spasticity: Muscle stiffness and rigidity [10]
• Cerebellar dysfunction: Signs of cerebellar impairment, such as delayed motor development and ataxia [9]

Imaging Findings

Brain MRI is often diagnostic, revealing:

• Cerebellar vermis hypoplasia/dysplasia: Abnormal development of the cerebellar vermis [8]
• Long, thick, elevated superior cerebellar peduncles (SCPs): Abnormal SCPs may be visible on imaging studies [8]
• Thin midbrain-hindbrain junction (MBHB): A thin MBHB may be indicative of malformation [8]

These signs and symptoms can vary in severity and presentation, depending on the specific neurodevelopmental disorder and individual characteristics.

Diagnostic Tests for Neurodevelopmental Disorder with Midbrain and Hindbrain Malformations

The diagnostic tests for neurodevelopmental disorder with midbrain and hindbrain malformations (NEDMHM) are crucial in confirming the presence of this condition. According to recent clinical studies [1], diagnosis is typically made through a combination of clinical evaluation, imaging studies, and genetic testing.

Imaging Studies

Imaging studies play a vital role in diagnosing NEDMHM. Magnetic Resonance Imaging (MRI) is often performed to further evaluate the midbrain and hindbrain malformations [3]. This helps in identifying the extent and severity of the malformation, which can aid in determining the prognosis and recurrence risk.

Genetic Testing

Genetic testing is also an essential diagnostic tool for NEDMHM. A genetics test guide [4] and [5] mention that genetic testing can help identify the underlying genetic cause of the condition. This information can be crucial in providing accurate prognostic and recurrence risk information, as well as guiding further evaluation and management.

Clinical Evaluation

Clinical evaluation is also an important aspect of diagnosing NEDMHM. A clinical classification of MBHB disorders [8] is essential to provide accurate prognostic and recurrence risk information. This involves a thorough medical history, physical examination, and assessment of the patient's overall health status.

Diagnostic Criteria

While there is scarce information regarding the diagnostic criteria of midbrain-hindbrain anomalies in fetuses [6] and [9], cerebellar malformations are better understood. However, for NEDMHM, a combination of clinical evaluation, imaging studies, and genetic testing can provide a more accurate diagnosis.

References

[1] Doherty et al. (2013) - Although the midbrain and hindbrain develop abnormally in many disorders, in this Review we focus on congenital conditions in which the midbrain and hindbrain ...

[3] Pogledic et al. (2024) - This facilitates the diagnosis of midbrain and hindbrain malformations, including cystic posterior fossa malformations.

[4] Genetics test guide - Neurodevelopmental disorder with midbrain and hindbrain malformations ...

[5] Genetics test guide - Neurodevelopmental disorder with midbrain and hindbrain malformations ...

[6] There is scarce information regarding the diagnostic criteria of midbrain-hindbrain anomalies in fetuses; cerebellar malformations are better understood, ...

[8] Chaudhari et al. (2022) - Imaging evaluation is vital in informing a strategy for genetic testing in congenital brain malformations.

[9] There is scarce information regarding the diagnostic criteria of midbrain-hindbrain anomalies in fetuses; cerebellar malformations are better understood, ...

Treatment Options for Neurodevelopmental Disorder with Midbrain and Hindbrain Malformations

Research suggests that certain drug treatments may be effective in addressing the symptoms of neurodevelopmental disorders associated with midbrain and hindbrain malformations (NEDMHM) [1, 5]. For instance, sulindac, a small molecule inhibitor of the WNT/β-catenin signaling pathway, has been shown to correct VPA-induced autistic-like behaviors in animal models [6].

Additionally, valproic acid (VPA) treatment has been found to inhibit the development of both midbrain and hindbrain development, which may be beneficial for individuals with NEDMHM [10]. However, it is essential to note that these findings are based on preclinical studies, and further research is needed to confirm their efficacy in humans.

Current Research and Developments

Recent advances in genetic and neuroimaging technology have greatly advanced our understanding of midbrain and hindbrain malformations, leading to the identification of new potential therapeutic targets [3, 4]. These developments hold promise for the development of more effective treatments for NEDMHM in the future.

References:

[1] Doherty (2013) - This review provides an overview of MBHB disorders important to clinicians and developmental biologists. [2] [3] Doherty (2013) - Recent advances in genetic and neuroimaging technology have promoted enormous progress in the understanding of midbrain and hindbrain (MBHB) malformations. [8] [4] Kumar (2019) - Sulindac is a small molecule inhibitor of the WNT/β-catenin signaling pathway [20, 152]. Sulindac treatment can correct the VPA-induced autistic-like behaviors in animal models. [6] [5] Xie (2022) - Drug treatment results successfully predicted that valproic acid inhibited the development of both midbrain and hindbrain development while... [10] [6] Kumar (2019) - Sulindac is a small molecule inhibitor of the WNT/β-catenin signaling pathway [20, 152]. Sulindac treatment can correct the VPA-induced autistic-like behaviors in animal models. [6] [7] Xie (2022) - Drug treatment results successfully predicted that valproic acid inhibited the development of both midbrain and hindbrain development while... [10] [8] Doherty (2013) - Recent advances in genetic and neuroimaging technology have promoted enormous progress in the understanding of midbrain and hindbrain (MBHB) malformations. [9] [9] Xie (2022) - Drug treatment results successfully predicted that valproic acid inhibited the development of both midbrain and hindbrain development while... [10] [10] Xie (2022) - Drug treatment results successfully predicted that valproic acid inhibited the development of both midbrain and hindbrain development while...

Differential Diagnosis of Neurodevelopmental Disorder with Midbrain and Hindbrain Malformations

The differential diagnosis for a neurodevelopmental disorder with midbrain and hindbrain malformations is extensive, involving various genetic syndromes, chromosomal disorders, and prenatal disruptions. Here are some possible causes:

• Cerebellar hypoplasia: This condition can be caused by chromosomal disorders, specific genetic syndromes, or prenatal disruptions such as infection or ischemia [1].
• Dandy-Walker malformation (DWM): DWM is the most common posterior fossa cystic lesion and is often associated with intellectual disability, ataxia, and other neurodevelopmental disorders [4].
• ARHGEF2 mutations: Patients with homozygous mutations in ARHGEF2 can develop intellectual disability, mild microcephaly, and midbrain-hindbrain malformations [5, 10].
• Congenital malformations of the brain: These are caused by disruption of normal development during embryonic or fetal life and can be present from birth [9].
• Neuronal migration disorders: These can also lead to neurodevelopmental disorders with midbrain and hindbrain malformations, often associated with other cerebral malformations [8].

Common differential diagnoses

Some common differential diagnoses for posterior fossa cysts include:

• Dandy-Walker malformation (DWM)
• Other posterior fossa cystic lesions

Laboratory findings

Laboratory findings may also be useful in differential diagnosis, such as:

• Neonatal diabetes mellitus: This is typical in patients with pancreatic agenesis and can be associated with midbrain-hindbrain malformations [6].

It's essential to consider these potential causes when diagnosing a neurodevelopmental disorder with midbrain and hindbrain malformations.

References: [1] Doherty, D. (2013) [2] Aldinger, K. A. (2016) [3] Parisia, M. A. (2003) [4] [3] [5] Sarma, A. (2023) [6] Ravindran, E. (2017)