(1) Background: The characteristics of rare diseases (RDs) vary considerably—not only
between different disease types but also between individual patients with the same
condition. In the Roma community, we analyzed the most frequent rare genetic disorders
related to the founder effect. (2) Methods: This retrospective study, conducted between
January 2019 and January 2025 at the Clinical Genetics and Metabolics Outpatient Clinic
in Košice, included 61 patients aged from infancy to 25 years diagnosed with hypomyelinating
leukodystrophy 14, pontocerebellar hypoplasia type 1B, neuronal ceroid lipofuscinosis
7, or TMEM70 deficiency. (3) Results: This study includes the largest known cohort
of patients with hypomyelinating leukodystrophy 14 caused by the UFM1 c.-273_-271delTCA
mutation, predominantly affecting males (n = 17). The disorder is severe, with most
patients dying before one year of age, and is characterized by inspiratory stridor,
axial hypotonia, spastic quadriparesis, pseudobulbar signs, and microcephaly. In a
separate group with pontocerebellar hypoplasia type 1B, six Roma patients (three males,
three females) shared the same EXOSC3 mutation. Diagnosis occurred at an average age
of 8.8 months, and most children did not survive beyond three years. Common features
included microcephaly, severe hypotonia, and spastic quadriplegia. Thirteen children
from eight families were diagnosed with neuronal ceroid lipofuscinosis 7, all carrying
the same MFSD8 mutation. Symptoms typically began with psychomotor regression between
ages 3 and 4, along with intellectual disability and seizures, which were more frequent
in males. The mean age at diagnosis was 4.5 years, and eight children died before
age nine. Finally, 25 patients with TMEM70 deficiency associated with Roma ancestry
were identified, predominantly females, with a mean age of 9.95 years and the oldest
patient aged 25. Four children died due to severe metabolic crises. Common findings
included intellectual disability, global hypotonia, hypertrophic cardiomyopathy, epilepsy,
and failure to thrive. (4) Conclusions: Most rare diseases are genetic and carry high
morbidity and mortality, with no targeted therapies currently available. Their increased
prevalence in the Roma population reflects founder effects and high consanguinity.
Prenatal and newborn screening, along with voluntary carrier testing for couples,
is essential for proactive health management.
