Charcot-Marie-Tooth Disease
Charcot-Marie-Tooth disease (CMT) also known as Charcot–Marie–Tooth
neuropathy is a heterogeneous group of disorders characterized by distal muscle
weakness and atrophy and loss of sensation in the feet and/or hands. Usually, theinitial symptoms are foot deformities, such as high arches and hammertoes and“inverted champagne bottle” appearance of the lower parts of the legs. Weaknessand muscle atrophy may occur in the hands as the disease progresses. Other
symptoms of the disease may include hearing loss and scoliosis.
Prevalence of CMT hereditary neuropathy is about 1:2500.
Based on clinical manifestations and affected genes, CMT can be divided into types
and subtypes. The most common form of CMT is Charcot-Marie-Tooth type 1A
caused by duplication of or mutation in the PMP22 gene.
CMT neuropathy can be inherited in an autosomal dominant, autosomal recessive,or X-linked manner.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling

Cornelia de Lange Syndrome
Cornelia de Lange syndrome (CdLS) is characterized by distinctive facialfeatures, growth retardation, developmental delay, hirsutism, and limb
abnormalities. Craniofacial features include synophrys, arched eyebrows, longeyelashes, small upturned nose and thin downturned lips, small widely spaced
teeth, and microcephaly.
Additional findings may include cardiac defects, gastrointestinal dysfunction,
hearing loss, myopia, seizures, cleft palate, and cryptorchidism or hypoplastic
genitalia.
The prevalence of disorder is estimated at 1:50,000 for the classic form of CdLS.
CdLS can be inherited in an autosomal dominant or X-linked manner.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing of at-risk female relatives
3. Prenatal diagnosis for known familial mutation
4. Genetic counselingMenkes Disease
Menkes disease is a disorder of copper metabolism characterized by growth
failure, developmental delay and progressive neurodegeneration. Patients withMenkes disease may also present hair changes (short, sparse, coarse, twisted hair,and colorless or steel-colored), hypothermia, hypoglycemia, hypotonia, andseizures. Onset of Menkes disease typically begins in the neonatal period.
Menkes disease is caused by mutations in the ATP7A gene. The disorder isinherited in an X-linked recessive pattern.
The incidence of Menkes disease is estimated to be 1 in 100,000 to 360,000
newborns.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling
4. Prenatal diagnosis for known familial mutation

Microcephaly
Microcephaly is a neurological condition characterized by occipito-frontal headcircumference at birth equal to or less than -2 SD below the mean for sex, age, andethnicity. Clinical findings may also include abnormal brain structure, cognitive
impairment, short stature, craniosynostosis and seizures.
Microcephaly is considered primary, which is present at birth and secondary, whichd e v e l o p s p o s t n a t a l l y. B o t h p r i m a r y m i c r o c e p h a l y a n dsecondary microcephaly can be isolated, syndromic or associated with otherbrain malformations. Genetic conditions with microcephaly involvement
includeCornelia de Lange syndrome, Seckel syndrome, Smith-Lemli-Opitz
syndrome, syndromes associated with chromosomal abnormatlities, and DNA
repair disorders.
The inheritance patterns of microcephaly can be autosomal dominant, recessive or
x-linked.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Differential diagnosis
3. Carrier testing for at-risk relatives
4. Prenatal diagnosis for known familial mutation
5. Genetic counselingMitochondrial Diseases
Mitochondrial diseases are a genetically and clinically heterogeneous group ofdisorders that arise as a consequence of dysfunction of the mitochondrial
respiratory chain. The estimate for the prevalence of all mitochondrial disorders
1:8500, but they are thought to be greatly under-diagnosed. Mitochondrial disorders
can be caused by mutations of nuclear or mitochondrial DNA (mtDNA). If nuclear
gene defects may be inherited in an autosomal recessive or autosomal dominantmanner, mtDNA defects are transmitted only maternally. As the female could haveheteroplasmic mtDNA mutations, which could be transmitted unequally to heroffspring, the sibs could exhibit considerable clinical variability.
Symptoms of the mitochondrial disease can begin at any age. Mitochondrial
disorders may affect a single organ (e.g. Leber hereditary optic neuropathy,LHON) or involve multiple organ systems (e.g.Myoclonic epilepsy with ragged-redfibers, MERRF). Common clinical features of mitochondrial disorder include, forexample muscle weakness, exercise intolerance, trouble with balance andcoordination, sensorineural deafness, impaired vision, seizures and learning
deficits, cardiomyopathy, diabetes mellitus, stunted growth, and a high incidence ofmid- and late pregnancy loss.
1. Diagnosis of patients with phenotype characteristic for mitochondrial disease
2. Diagnosis of patients with family history suggestive for mitochondrial disease
3. Genetic counseling of individuals with mitochondrial disease and affected family
members
Genetic testing of mitochondrial disease may be carried out on:
DNA extracted from blood (in case of suspected nuclear DNA mutations andsome mtDNA mutations), or
DNA extracted from muscle (in case of suspected mtDNA mutations as
pathogenic mtDNA mutations may not be detected in DNA extracted fromblood [2]).

Smith-Lemli-Opitz Syndrome
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessively inheritedmultiple malformation syndrome due to an inborn error cholesterol synthesis –insufficiency of enzyme 7-dehydroxycholesterol reductase. The syndrome ischaracterized by intrauterine and also postnatal growth retardation, moderate tosevere mental retardation, malformations in many organ systems (cardiovascular,urogenital, gastrointestinal and central nervous systems). The patients have acharacteristic appearance: ptosis, polydactyly, syndactyly of the II and III toes onboth feet.
The incidence of SLOS is 1:20,000-70,000. SLOS is associated with mutations in
the DHCR7 gene.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling
4. Prenatal diagnosis

Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized bymuscle weakness and atrophy resulting from progressive degeneration and loss of
the lower motor neurons in the spinal cord and the brain stem nuclei. Theweakness is almost always symmetric and progressive. Poor weight gain,pneumonia, sleeping problems, scoliosis, and joint contractures are common
symptoms of SMA.
Spinal muscular atrophy is divided into five subtypes (SMA 0, SMA I, SMA II, SMA
III, SMA IV), distinguished by the age of onset and maximum function attained.
SMA is inherited in an autosomal recessive manner. Disease incidence rate is 4-10
per 100,000 live births.
Indications for genetic testing:
1. Differential diagnostics
2. Carrier testing for at-risk relatives
3. Prenatal testing for known familial mutations
4. Genetic counselingWilson Disease
Wilson disease (WD) is an autosomal recessive inherited disorder characterized
by the toxic accumulation of copper in various organs including the liver, the cornea
and the brain, causing damage therein. The disorder usually manifests in thesecond decade of life and the hepatic form usually appears earlier than theneurological form. Wilson disease is caused by mutations in theATP7B gene.
Indications for genetic testing:
1. Confirmation of clinical diagnosis
2. Carrier testing for at-risk family members
3. Genetic counseling