Common Neurogenetic Syndromes
Anna L. Pinto
Jurriaan M. Peters
Genetics has become a promising and active research and clinical field within neurology. This young discipline applies molecular genetic techniques to the investigation of classical neurological disorders and symptoms. Novel genetic and metabolic tests are increasing the ability to provide an etiologic diagnosis for children with unexplained global developmental delay and deficits in intellectual development. A genetic etiology should be suspect in all patients who present with developmental delay, autism spectrum disorder (ASD), epilepsy, abnormal head size or shape, movement disorders, as well as dysmorphic features. Given the complexity and costs of genetic testing, clinicians should aim for a rational approach to an accurate etiologic diagnosis focusing on initial tests with high diagnostic yield.
PATTERNS OF INHERITANCE
Single Gene (Mendelian)
(1) AUTOSOMAL: Then defective gene is on a non-sex chromosome.
Dominant (AD): Monogenic AD disorders occur through the inheritance of a single copy of a defective gene found on a non-sex chromosome. The single defective copy is sufficient to override the normal functioning copy, resulting in abnormal protein functioning or expression.
Recessive (AR): Monogenic AR disorders occur through the inheritance of both copies of the defective gene, one from each parent.
(2) X-LINKED: The defective gene lies on the × sex chromosome.
Dominant (XD): Less frequent than recessive, both males and females can be affected. The exact pattern of inheritance varies, depending on whether the father or the mother has the trait of interest. All daughters of an affected father will also be affected, but none of his sons will be affected; and the mother of an affected son is also affected.
Recessive (XR): A female with a gene mutation on one X chromosome would be a carrier. On average, 50% of her sons will inherit the mutation and develop the disorder, and 50% of her daughters will inherit the mutation and become a carrier.
Non-Mendelian
(1) MULTIFACTORIAL INHERITENCE: >1 genetic factor is involved in developing a specific condition, and environmental (epigenetic) factors also participate in the causation of a disease.
(2) MITOCHONDRIAL INHERITANCE: Mitochondria contain their own DNA (mtDNA), distinct from nuclear (chromosomal) DNA. Mutation in the mitochondrial DNA can only be transmitted by the mothers to male or
female offspring. Not all mitochondrial disease comes from mtDNA; mutations in nuclear genes that code for mitochondrial proteins may be inherited in an AD, AR, or X-linked fashion.
female offspring. Not all mitochondrial disease comes from mtDNA; mutations in nuclear genes that code for mitochondrial proteins may be inherited in an AD, AR, or X-linked fashion.
(3) MISCELLANEOUS: Genomic imprinting is when differential monoallelic expression of a biallelic gene occurs, depending on the male or female parental origin of gene. Thus, with the silencing of imprinted alleles, there is no biparental contribution to the genome. This is done through DNA methylation (see below) or histone modifications. Uniparental disomy (UPD) occurs when both chromosome pairs come from a single parent. DNA methylation causes modification of regulation of gene expression without altering the DNA sequence. Somatic mosaicism occurs when different genotypes arise from a single fertilized egg cell, due to mitotic errors at first or later cleavages.
DIAGNOSTIC TOOLS
DETECTING CYTOGENETIC ABNORMALITIES: Chromosomal number and rearrangements can be tested at both structural and molecular levels. Karyotype (or chromosome) analysis enables the entire chromosome structure to be viewed at one time, but only detects aneuploidies and major structural rearrangements. Fluorescence in situ hybridization (FISH) is a molecular technique using specific loci-labeled probes spaced throughout the genome, and has higher sensitivity, specificity, and resolution, compared with chromosome analysis; however, small mutations and UPD can be missed. Chromosomal microarray analysis (CMA), also called comparative genomic hybridization (CGH) or array CGH (aCGH), is increasingly the first-line test of genetic screening and can be used in targeted conditions or applied to the whole genome for identification of copy number variation (CNV), including deletion/duplication. However, balanced structural rearrangements and small amounts of mosaicism can be missed. Methylation studies detect DNA methylation.
DETECTING MUTATIONS: Done with targeted tests or gene panels based on phenotype, and thus typically limited to a predefined number of sequence changes selected in advance. Polymerase chain reaction (PCR) is the 1st step in the vast majority of DNA analysis. Amplification refractory mutation system (ARMS) is a modified PCR technique, requiring a multiplex PCR reaction. Single nucleotide polymorphism (SNP) arrays detect the most common type of genetic variation among people, and may assist in the prediction of an individual’s response to certain drugs (pharmacogenetics), susceptibility to environmental factors such as toxins, and risk of developing particular diseases. Multiplex ligation-dependent probe amplification (MLPA) has become a rapidly growing technique used in the detection of exon deletion. Whole exome sequencing is a highly advanced test developed for the identification of DNA changes causative or related to a medical condition in a patient. Exons or coding regions of thousands of genes are analyzed simultaneously using next-generation sequencing techniques. Interpretation of the results requires considerable expertise, and mapping the function of the entire human genome is a work in progress.
COMMON SPECIFIC CYTOGENETIC SYNDROMES
Trisomy 211 (Down Syndrome, DS)
EPIDEMIOLOGY: Most common autosomal anomaly and most common single cause of mental retardation. Incidence ˜1 in 1,000 newborns, strongly associated with advanced maternal age (≥35 y).
GENETICS: Trisomy 21 is most common. Nonreciprocal translocation (˜10%, often chromosome 21 to chromosome 14) has same clinical phenotype. Mosaicism (2%-3%) is associated with a higher intellectual development. Karyotype analysis shows presence of an extra chromosome 21 in all or some percentage of somatic cells. Recurrence/mode of inheritance in siblings of true trisomy is rare (<1%), and recurrence of translocation is more common (5%-15%).
PATHOPHYSIOLOGY: Thought to be in part related to overexpression of 21q22 region with a DS cell adhesion molecule (DSCAM, role in neuronal migration, axon guidance, neural connectivity) and a protein kinase (DYRK1, role in postembryonic neuronal cell proliferation).
CLINICAL PRESENTATION: Unusual association of common anomalies: facial dysmorphism (brachycephaly, flat nasal bridge, laterally upslanting and narrow palpebral fissures, epicanthal folds, simple C-shaped ear with deficient cartilage and narrow external auditory canal, open mouth with prominent protruding fissured tongue, low posterior hairline), physical habitus (short stature and neck, excessive skin at nape of neck, obesity, hypotonia with lax joints, broad hands with single palmar crease, brachy- and 5th-digit clinodactyly, wide 1-2 toe gap). Mental retardation (IQ, 25-49; average 43) with social skills better than expected from their IQ. Note that an adult with DS is considered competent to make medical decisions unless declared otherwise. Multisystem involvement: See Table 10.1.
TABLE 10.1 Down Syndrome: Common Associated Anomalies and Management | |||||||||||||||||||||||||||||||||||||||||||||||
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PRESENILE DEMENTIA: Increasing prevalence with age (3rd decade, 10%; 4th, 10%-25%; 5th, 28%-55%; 6th, 30%-75%). Early signs and symptoms include speech and gait deterioration, later include adult-onset seizures and myoclonus, apathy, behavioral or personality change, psychiatric comorbidity, focal neurological signs, urinary and fecal incontinence, sleep disorders, cognitive and memory impairment. Pathophysiology parallels Alzheimer disease (AD) with overexpressed amyloid-β precursor protein from 21q21 region. Gender (male), estrogen deficiency, elevated expression of beta-site APP-cleaving enzymes (BACE), valine polymorphism of prion protein gene, and carriers of apolipoprotein E4 allele may have accelerated decline. Imaging may show premature aging, calcifications of basal ganglia, and cerebellar folia; age-related atrophy resembles the pattern of brain atrophy in early stages of AD. Management and diagnosis are not specific to DS.
PROGNOSIS: Multiple factors affect outcome, including associated conditions. Life expectancy is in the mid-50s. Many people with this syndrome form meaningful relationships and eventually marry.
Klinefelter Syndrome2
EPIDEMIOLOGY: Affects 1 in 500 to 1,000 males and does not occur in females.
GENETICS: 47,XXY variant is found in 80% to 90% of patients, and about 10% of patients will have mosaicism. Karyotypes include 46,XY/47,XXY; 46,XY/48,XXXY; and 47,XXY/48,XXXY.
PATHOPHYSIOLOGY: Involves the extranumerary × chromosome whose genes play roles in many body systems, including testicular function, brain development, and growth. As the number of × chromosome increases, somatic and cognitive developments are more likely to be affected. Whether the morbidity associated with the syndrome results from the hormonal abnormalities or abnormal function of the × chromosome-linked genes is unclear. Besides cytogenetic analysis, androgen receptor gene quantitative real-time PCR (AR-qPCR) is a reliable screening method for disorders involving aberrant number of × chromosome. The recurrence risk is not increased above that in the general population.
CLINICAL PRESENTATION: Shortage of testosterone is associated with small testes, gynecomastia, reduced facial and body hair, and infertility. In addition, patients can present with tall stature, narrow shoulders, broad hips, osteoporosis, varicose veins, thromboembolic disease, or diabetes mellitus. Neurologically, epilepsy, learning disabilities, and difficulty with speech and language development are seen.
MANAGEMENT: Multidisciplinary team approach should address three major aspects of the disease: hypogonadism, gynecomastia, psychosocial and developmental problems (including speech impairment, academic difficulties, and behavioral problems). Monitoring and health maintenance: Endocrinology for testosterone replacement therapy, routine bone density screening for risk of osteopenia and osteoporosis. Hypercoagulability screening, given the increased risk for deep venous thrombosis and pulmonary embolism. Adult males have an increased risk of developing breast cancer and immunologic disease such as systemic lupus erythematosus.
PROGNOSIS: Generally good; patients are at risk for developing the aforementioned comorbidity.
22q11.2 Microdeletion Syndromes (DiGeorge and Velocardiofacial Syndrome,3 and Phelan/McDermid Syndrome5)
EPIDEMIOLOGY: Prevalence ˜1:5,000 (velocardiofacial [VCF]) and ˜1: 2-4,000 (DiGeorge).
GENETICS: Most frequent microdeletion of 22q11.2. High-resolution chromosome analysis; FISH for a chromosome region 22q11 deletion. Recurrence will depend on the parental status. Parental carrier frequency is ˜10%. Most patients carry a de novo mutation. If DiGeorge is suspected but testing is negative, consider TBX1 gene sequencing and consult with clinical geneticist.
PATHOPHYSIOLOGY: The microdeletion includes genes that affect, in part, the migration of neural crest cells and early development of the branchial arches.
CLINICAL PRESENATION: Velo (69%; overt or submucous cleft palate, velopharyngeal insufficiency with rhinolalia aperta), cardio (conotruncal defects, including tetralogy of Fallot, ventricular septal defect, interrupted aortic arch, and truncus arteriosus), facial (prominent bulbous nose w/ squared root, hypertelorism, micrognathia), and parathyroid deficiency with hypocalcemia (20%). Immunodeficiency (77%), feeding problems (30%), renal anomalies (37%), conductive and sensorineural hearing loss, laryngotracheoesophageal anomalies, growth hormone deficiency, autoimmune disorders, seizures (without hypocalcemia), and skeletal abnormalities. Neurologically, learning difficulties or mild mental retardation (MR; 70%-90%). Associated with perisylvian and frontal polymicrogyria and epilepsy. Associated with a variety of psychiatric disorders, including schizophrenia. DiGeorge syndrome4 involving thymic hypoplasia and hypocalcemia at birth is also a common finding, clinically one sees to feeding difficulties (poor sucking and swallowing problems). Immunodeficiency of the T-cell lines. Facial features include low-set ears, hypertelorism, and narrow upper lip. Neurological manifestations include global development delay, learning disabilities, and hypotonia. Monitoring and health maintenance includes absolute lymphocyte count in the peripheral blood; ionized calcium and parathyroid hormone level. Mental health care for ADHD, depression, and other behavioral disorders.
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