The analysis of genetic aberrations in children with inherited neurometabolic and neurodevelopmental disorders
Krystyna Szymańska1, Krzysztof Szczałuba2, Agnieszka Lugowska3
1Department of Clinical and Experimental Neuropathology, Mossakowski Medical Research Centre, Polish Academy of Sciences, 02-106 Warsaw, Poland ; Department of Child Psychiatry, Medical University of Warsaw, 00-576 Warsaw, Poland.
Insights
Genetic testing is crucial for diagnosing rare inherited pediatric brain disorders when standard methods fail. This study highlights how advanced genetic analysis identified specific mutations in seven children, leading to accurate diagnoses.
Area of Science:
- Genetics and Genomics
- Neurology
- Pediatrics
Background:
- Inherited encephalopathies are diverse and challenging to diagnose.
- Clinical, laboratory, and MRI findings are often insufficient for definitive diagnosis.
- Genetic testing is essential for identifying the underlying causes of these complex disorders.
Purpose of the Study:
- To investigate the utility of integrated genetic testing in diagnosing difficult pediatric encephalopathies.
- To identify specific genetic causes in seven patients with undiagnosed inherited brain disorders.
- To discuss the diagnostic approach for complex hereditary neurological conditions.
Main Methods:
- Performed cytogenetics, PCR-based tests, and array-based comparative genome hybridization.
- Analyzed genetic data from seven pediatric patients with undiagnosed encephalopathies.
- Integrated genetic findings with clinical, laboratory, and MRI data.
Main Results:
- Identified microduplication in 16q23.1 (WWOX, MAF genes) in one patient with language impairment.
- Diagnosed Smith-Magenis syndrome (17p11.2 deletion) in two patients.
- Confirmed DYT1 deletion in a patient with torsion dystonia and identified GALC variants in a Krabbe disease case.
Conclusions:
- An integrated diagnostic approach combining clinical evaluation with advanced genetic testing is vital for rare inherited encephalopathies.
- Genetic analysis successfully identified causative mutations in challenging pediatric neurological cases.
- This strategy improves diagnostic accuracy and informs patient management for complex brain disorders.
Abstract:
Inherited encephalopathies include a broad spectrum of heterogeneous disorders. To provide a correct diagnosis, an integrated approach including genetic testing is warranted. We report seven patients with difficult to diagnose inborn paediatric encephalopathies. The diagnosis could not be attained only by means of clinical and laboratory investigations and MRI. Additional genetic testing was required. Cytogenetics, PCR based tests, and array-based comparative genome hybridization were performed. In 4 patients with impaired language abilities we found the presence of microduplication in the region 16q23.1 affecting two dose-sensitive genes: WWOX (OMIM 605131) and MAF (OMIM 177075) (1 case), an interstitial deletion of the 17p11.2 region (2 patients further diagnosed as Smith-Magenis syndrome), and deletion encompassing first three exons of Myocyte Enhancer Factor gene 2MEF2C (1 case). The two other cases represented progressing dystonia. Characteristic GAG deletion in DYT1 consistently with the diagnosis of torsion dystonia was confirmed in 1 case. Last enrolled patient presented with clinical picture consistent with Krabbe disease confirmed by finding of two pathogenic variants of GALC gene and the absence of mutations in PSAP. The integrated diagnostic approach including genetic testing in selected examples of complicated hereditary diseases of the brain is largely discussed in this paper.
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