Most common form of X-linked mental retardation.
Affects males more often and more severely than females. Only subtle
dysmorphic features. Behavioral issues may be more pronounced.
FRAXA Syndrome; Martin Bell Syndrome; X-linked Mental
Retardation with Macroorchidism.
The incidence for boys is estimated to be 1:1000-5000
live births, making it the most common chromosomal cause of mental
retardation second only to trisomy 21. The clinical picture can vary
Inheritance is X-gonosomal dominant. The
genetic defect has been mapped to Xq27.3. Advanced maternal age seems to be
a risk factor for this disorder.
The clinical picture may be suggestive of the disease,
although the dysmorphic features are rather subtle. The diagnosis can be
confirmed using molecular genetic testing (Southern blot) and relies on the
detection of an altered fragile X mental retardation-1 (FMR1) gene. In almost
all patients, the mutation is caused by a significantly increased number of
CGG (C = cytosine, G = guanosine) trinucleotide repetitions, which is also
associated with abnormal methylation of the FMR1 gene. The absence of or
mutation in the fragile mental retardation protein (FMRP) is responsible for
the Fragile X syndrome. FMRP is an RNA binding protein that shuttles between
the nucleus and the cytoplasm. It seems that FMRP is located at synapses,
where it is involved in signal transduction and encoding of cytoskeletal
proteins. It also appears that lack of FMRP affects synaptic plasticity.
Prenatal diagnostic is possible.
This progressive X-linked mental retardation
affects boys (moderate mental retardation) more often and more severely than
girls (mild mental retardation). The main neurologic symptoms include
delayed language skills, delayed motor development, autism or autistic-like
behavior, behavioral problems (attention deficit hyperactivity disorder,
oppositional defiant disorder, enuresis, encopresis), and poor sensory
skills. Anatomical features may include macrocephaly, a long face with
prognathism (which in fact is often just a prominent symphysis of the
mandibula rather than real prognathism), strabismus, prominent large ears,
high arched palate, and a high-pitched voice. The external male genitalia
show pronounced growth during puberty, which results in macroorchidism.
Overall, muscle tone is low with generalized joint laxity (particularly of
the fingers). Pectus excavatum, flat feet, shortening of the tubular bones
of the hands, and hyperlordosis may be present. Heart defects (e.g., mitral
valve prolapse), dilatation of the aortic root, and seizures have been
described. Researchers found that the hippocampus often shows an age-related
increase in size, whereas the superior temporal gyrus and the posterior
cerebellar vermis are diminished in size. After age 50 years, patients show
an increased rate of progressive parkinsonism, cognitive decline, and
generalized brain atrophy.
The cardiovascular findings may
prompt the anesthetist to request an echocardiography. If pectus excavatum
is present and significant, a chest radiograph should be obtained. Because
these patients are mentally retarded and may have some additional behavior
issues, preoperative sedation is most often helpful and therefore
Careful positioning and ...