Abstract
Hereditary spastic paraplegias (HSPs) are a heterogeneous group of genetic disorders with spastic paraparesis as the main clinical feature. Complex forms may co-occur with other motor, sensory, and cognitive impairment. A growing number of loci and genes are being identified, but still more than 50% of the patients remain without molecular diagnosis. We present a Spanish family with autosomal dominant HSP and intellectual disability (ID) in which we found a possible dual genetic diagnosis with incomplete penetrance and variable expressivity in the parents and three siblings: a heterozygous duplication of 15q11.2–q13.1 found by array CGH and a novel missense heterozygous change in REEP1 [c.73A>G; p.(Lys25Glu)] found by whole exome sequencing (WES). Following the standard genetic diagnosis approach in ID, array CGH analysis was first performed in both brothers affected by spastic paraparesis and ID from school age, and a heterozygous duplication of 15q11.2–q13.1 was found. Subsequently, the duplication was also found in the healthy mother and in the sister, who presented attention deficit/hyperactivity disorder (ADHD) symptoms from school age and pes cavus with mild pyramidal signs at 22 years of age. Methylation analysis revealed that the three siblings carried the duplication unmethylated in the maternal allele, whereas their mother harbored it methylated in her paternal allele. Functional studies revealed an overexpression of UBE3A and ATP10A in the three siblings, and the slightest cognitive phenotype of the sister seems to be related to a lower expression of ATP10A. Later, searching for the cause of HSP, WES was performed revealing the missense heterozygous variant in REEP1 in all three siblings and the father, who presented subtle pyramidal signs in the lower limbs as well as the sister. Our findings reinforce the association of maternally derived UBE3A overexpression with neurodevelopmental disorders and support that a spectrum of clinical severity is present within families. They also reveal that a dual genetic diagnosis is possible in patients with presumed complex forms of HSP and cognitive impairment.
Highlights
Hereditary spastic paraplegias (HSPs) are a heterogeneous group of genetically determined disorders with progressive spastic paraparesis as the main clinical feature [1, 2]
We describe a non-consanguineous family with three siblings, two of them males with intellectual disability and spastic paraparesis and one female with behavioral problems and pes cavus (Figure 1)
The break-points are in accordance with those reported as “Type II” by Roberts et al [11] going from the breakpoints BP2 to BP3 (Figure 2B) and including the Prader–Willi/Angelman critical region (PWACR) and a cluster of imprinting genes involved in those syndromes (UBE3A and ATP10A, GABRB3, GABRA5, and GABRG3)
Summary
Hereditary spastic paraplegias (HSPs) are a heterogeneous group of genetically determined disorders with progressive spastic paraparesis as the main clinical feature [1, 2]. Patient III-4 (Figure 1) is a 22-year-old female, with normal pregnancy, delivery, and neurodevelopment during the first years of life She accepted to be evaluated for genetic counseling following familiar molecular studies. An ADHD (attention deficit/hyperactivity disorder) diagnosis was made starting from 8 years old, with normal IQ From teenage she referred social anxiety symptoms, clumsiness, and feet pain with long walks. At the age of 22, physical examination revealed pes cavus with brisk tendon reflexes and mild pyramidal signs, without muscle wasting, spasticity, or low vibration sense. Physical examination revealed subtle pyramidal signs in the lower limbs, with brisk tendon reflexes, Rossolimo sign but flexor plantar response and normal vibration sense He has mild pes cavus with normal NCS, SSEP, and TMS. In relation to information about maternal members, the mother reported that none of their relatives was diagnosed of a neurodegenerative disorder
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