Down syndrome (DS) has an approximate incidence of 1 in 650 births.¹⁴⁴ In 95% of cases, the cause is a nondisjunction of chromosomes 21 during meiosis; in about 4% of cases, there is an unbalanced translocation. Approximately 1% of patients are mosaics and show a less severe phenotype. The region that, if triplicated, results in the typical phenotype maps to 21q22.3.⁴¹ The risk of carrying a child with DS increases with increasing maternal age and with very young maternal age.⁷⁹

The main clinical features of this condition include growth retardation, mental retardation of variable degree, hypotonia, flat facies, brachycephaly with flat occiput, upward-slanting eyes, epicanthal folds, small ears, speckling of the iris (Brushfields spots), simian crease, and hypogonadism. About 40% of patients have congenital heart disease. There is a marked risk of leukemia. All individuals above the age of 35 years show features of Alzheimer disease.

Epilepsy in DS has been extensively investigated.^{45,60,66,83,135,147} The incidence of epilepsy in children with DS was estimated to be 1.4%.¹⁵³ However, the overall prevalence of epilepsy increases with age, reaching 12.2% in patients over 35 years
of age.¹⁵⁹ About 40% of patients have seizures since the first year of life, and another 40% experience their first seizure during the third decade.¹¹⁶ This trend seems to be related to the early medical complications of DS, such as hypoxic ischemic encephalopathy and congenital heart disease,¹²⁹ and the development of neuropathologic changes typical of Alzheimer disease³⁶ have a specific etiology, most often related to common medical complications of DS such as hypoxic–ischemic perinatal suffering, hypoxia from congenital heart disease, or infection. Febrile seizures have a low frequency (0.9%) in comparison with the general population.^{60,93,129,153} When only cases without known causes were considered, 2.5% of patients presented with seizures, a frequency still greater than that in the general population. Although many patients in both groups had their first seizure in the first year of life, seizures occurred significantly later in infants without a known etiology. Generalized tonic–clonic (GTC) seizures predominated in both the known and unknown etiology groups. Myoclonic seizures and infantile spasms with hypsarrhythmia were also common, the latter predominating in the unknown etiology group. Partial seizures usually occurred in patients with an identifiable etiology. Prognosis for recurrent seizures varied with the etiology. Patients with seizures related to cardiovascular disease were usually well controlled by anticonvulsants. Neonates with hypoxic–ischemic injury had poor outcomes. None of the patients who developed seizures as a result of CNS infection had persistent attacks. Patients with idiopathic seizures had generally good outcomes. The authors concluded that children with DS have an increased susceptibility to seizures early in life, and superimposed systemic illness increased the risk.

In a review of studies in which population estimates were possible, infantile spasms occurred in 0.6% to 13% of children with DS, representing 4.5% to 47% of all seizures (reviewed by Stafstrom and Konkol¹⁴⁶). Infantile spasms probably represent the most common seizure type in DS and, in most children, they appear without any evidence of additional brain damage.^{60,113,141,146} Prognosis is usually good with regard to seizure control. Remission was obtained on conventional antiepileptic drugs (AEDs), adrenocorticotropic hormone (ACTH), or steroids, without relapse of seizures^60,113,146 or with later onset of pharmacologically controllable, age-related generalized seizure disorders¹⁴¹ (Fig. 2). Conversely, spasms proved to be resistant, progressing to other forms of intractable epilepsy in most of the patients who suffered hypoxic insults.^60,146

The occurrence of reflex seizures in the context of startle epilepsy is particularly frequent (Fig. 3).^{54,66,115,130} Age at seizure onset is variable, and there is usually no evidence for etiologic factors other than DS. Most of the patients described presented “pure” forms of reflex epilepsies, with almost all seizures being precipitated by acoustic or tactile stimuli. However, the epileptic syndrome varied in type and severity, with a predominance of Lennox-Gastaut–type patterns.⁶⁶ The mechanism leading a high incidence of reflex phenomena in DS patients is unclear. A central deficit of inhibition of afferent stimuli has been proposed.²⁹

Lennox-Gastaut syndrome (LGS) has been well documented in DS, but is not frequent. Quite characteristic is its de novo appearance at a mean age of 10 years, not preceded by other forms of epilepsy.^60,66

Only a few studies have analyzed adult or late-onset epilepsy in DS, despite its high frequency.^90,159,164 Although in most late-onset epilepsies seizures appeared infrequently but were intractable,⁶⁰ no precise indications on seizure severity are available. Late-onset generalized epileptic myoclonus has also been reported.⁵³

Brain weight is in the lower normal range, and the gyral pattern is simplified.³⁹ A narrow superior temporal gyrus is observed in about 50% of patients. The insula is exposed because of hypoplasia of the inferior frontal gyrus.⁸⁶ Changes typical of Alzheimer disease appear above the age of 30 years.^51,64 Several cytoarchitectonic abnormalities have been found from birth, including a 20% to 50% decrease in the number of small granule cells, mainly inhibitory γ-aminobutyric acid (GABA)ergic interneurons, with lower neuronal density, abnormal neuronal distribution, and dysgenesis of dendritic spines.^{18,81,98,127,166} The relation among these structural abnormalities and increased susceptibility to certain seizure types, particularly infantile spasms and reflex seizures, is poorly understood.

Most patients have a free trisomy 21, detectable on standard chromosome analysis. In such circumstances, chromosome study in the parents is not indicated. Parents should be given a 1% recurrence risk, based on the calculation of the recurrence of DS in a sibship. This slightly higher recurrence risk, when compared to the expectation based on the maternal age is likely due to a germinal mosaicism present in a few parents or to a general failure in the chromosomal disjunction mechanisms normally occurring at meiosis.¹¹⁰

If DS results from a translocation, this usually occurs between acrocentric chromosomes, termed a robertsonian translocation. In such circumstances, one of the parents might be a balanced carrier of the translocation, and a chromosomal study is strongly indicated for both parents. The most common robertsonian translocation found in healthy carriers involves chromosomes 14 and 21. Virtually all the (21;21) translocations are de novo. The involvement of chromosome 21 in translocations with nonacrocentric chromosomes¹⁰¹ is very rare. The calculation of the recurrence risk for DS in the carriers of robertsonian translocation is based on the gender of the transmitting parent and the chromosome involved.

Fragile-X syndrome has an approximate incidence of 1 in 1,500 males¹⁶³ and is the most common chromosomal abnormality associated with heritable mental retardation. Both genders may be affected, but the phenotype is notably more severe in males. It is estimated that 1 in 1,000 females are carriers.²³ The X-chromosome of patients affected with the syndrome shows a “fragile” site at Xq27.3 when cells are grown in a folic-deprived medium. The condition results from a dynamic mutation in heritable unstable DNA,¹²⁴ because of variation in the copy number of a trinucleotide repeat p(CCG)n within the FMR1 gene. This fragile site is termed FRAXA. The disorder has an unusual mode of inheritance. About 20% of males who carry the mutation are clinically and cytogenetically normal (normal transmitting males). About 30% of female carriers have mental impairment. Transmission is consistent with an X-linked semidominant condition. The main clinical features include moderate mental retardation, poor language, hypotonia, growth retardation, macrocephaly, prominent forehead, long, narrow facies, large ears, macroorchidism, pectus excavatum, a floppy mitral valve, and hyperactive or autistic behavior.^50,165

The prevalence of epileptic seizures is approximately 25%.¹⁶⁷ Seizures usually appear before the age of 15 and tend to disappear during the second decade of life.^65,167 In most patients, seizures are fairly rare or are controllable with simple drug regimens.^{59,65,105,167} The most frequently mentioned seizure types are generalized tonic–clonic seizures.^50,165 However, no specific epilepsy syndrome is observed.⁶⁵ Background electroencephalographic (EEG) activity is slow.^105,167 An EEG pattern of midtemporal spikes, possibly age related, similar to the waveform of benign rolandic epilepsy, has been described in some affected males, with or without seizures.¹⁰⁴ This EEG pattern has been confirmed by other investigators, but only in a minority of cases.^60,167 The fragile-X locus has been excluded as the candidate gene for benign rolandic epilepsy.¹¹⁸

The variety in seizure types in the fragile-X syndrome may reflect extreme clinical polymorphism as a consequence of the variability of amplification of the trinucleotide repeat among patients.⁵² A somatic variation in DNA amplification during development is also possible.¹⁶⁸ Little is known of the neuropathology. Anomalous synapses and abnormal development of dendritic spines have been observed using Golgi impregnation.^129,167 Neuroimaging studies have shown hypoplasia of the cerebellar vermis¹²¹ and periventricular heterotopia in rare patients.¹⁰³

The fragile site at Xq27.3 is not expressed in cell culture media employed for standard karyotypes. The induction of the fragile site in stimulated lymphocytes can be achieved using culture media free of folic acid and thymidine. The fragile site is detected only in a proportion of metaphase cells, with most fragile-X males expressing their fragile site in only 5% to 50% of their lymphocytes. Normal transmitting males usually do not express the fragile site. Fragile-X females with mental impairment express their fragile site, but in a lower proportion of cells than do fragile-X males. The majority of female carriers do not express the fragile site, but some of them might show an expression in 5% or less of their cells. The fragile-X syndrome is due to the expansion of a p(CGG)n repeat within the 5′ untranslated region of the FMR1 gene. Normal chromosomes are polymorphic, containing 6 to 52 copies of this repeat, whereas males with more than 200 copies have the disease (full mutation). Normal transmitting males have 50 to 200 copies (premutation). Females bearing the premutation are phenotypically normal and do not express the fragile site. Females with more than 200 copies may be normal or mentally retarded and can show facial features of fragile-X syndrome. Premutations tend to expand when transmitted to offspring through female carriers, and the risk of expansion to a full mutation correlates with the size of the premutation.^52,73 In association with the full mutation, the promoter region of the FMR1 gene is hypermethylated, and the transcription of the gene is repressed.^112,160 DNA studies have improved the accuracy of testing for fragile-X syndrome. By looking at the size of the trinucleotide repeat segment, as well as the methylation status of the FMR1 gene, the genotype can be determined for both affected individuals and suspected carriers. Two main approaches are used: Polymerase chain reaction (PCR) and Southern blot analysis. PCR analysis utilizes flanking primers to amplify a fragment of DNA spanning the repeat region. Thus, the sizes of the PCR products are indicative of the approximate number of repeats present in each allele of the individual being tested. The efficiency of the PCR reaction is inversely related to the number of CGG repeats, so that large mutations are more difficult to analyze and may fail to yield a detectable product in the PCR assay. An additional limitation to the PCR approach is due to the fact that it provides no information about FMR1 methylation. On the other hand, PCR analysis permits accurate sizing of alleles in the normal and premutation size ranges. FMR1 analysis by Southern blotting allows both size of the repeat segment and methylation status to be assayed simultaneously. A methylation-sensitive restriction enzyme that fails to cleave methylated sites is used to distinguish between methylated and unmethylated alleles. Southern blot analysis is more labor intensive than PCR and requires larger quantities of genomic DNA. Southern blot accurately detects alleles in all size ranges, but precise sizing is not possible. Many laboratories can use both methods, and choose the type of analysis that is most appropriate to the circumstances. A few patients with fragile-X harboring deletions in the FMR1 have been described.^117,152

Two additional fragile sites reside in the distal Xq, termed FRAXE and FRAXF. Although FRAXF is not clearly associated with a specific phenotype, those with FRAXE show mental impairment, usually milder than that observed in patients with FRAXA mutations. Because no clinical overlap occurs between patients with mutations at the FRAXA and the FRAXE loci, other than mental retardation, the details about the diagnostic procedures for identifying FRAXE will not be discussed here.

Wolf-Hirschhorn syndrome (WHS) is a multiple congenital anomalies/mental retardation syndrome³⁴ with a frequency of 1 in 50,000 births and a female:male predilection of 2:1.^57,96 It is caused by partial loss of material from the distal portion of the short arm of chromosome 4. The minimal deleted segment causing the phenotype is 4p16.3.⁹⁶ Although about 75% of patients have a de novo deletion⁹⁶ of preferential paternal origin,^38,157 about 12% have an unusual chromosome abnormality (such as ring 4), and about 13% have a deletion of 4p16 resulting from an inherited unbalanced chromosome rearrangement from a parent with a balanced rearrangement. The main features of monosomy 4p are the typical “Greek warrior helmet appearance of the nose,” microcephaly, pre- and postnatal growth delay, congenital hypotonia, severe mental retardation, and seizures.¹³ In at least one-third of cases, death occurs during the first year of life because of severe systemic malformations, cardiac failure, or pulmonary infection.

Seizures constitute a major medical concern during the first years of life, and occur in 50% to 100% of patients.^{10,13,32,40,68,149} Seizure onset usually occurs within the first 2 years of life, with a peak incidence around 9 to 10 months of age. These seizures may be clonic or tonic, unilateral with or without secondary generalization, or generalized tonic–clonic from the onset.^{5,8,9,10,11,12,13,47,108,119} They are frequently triggered by fever, may be prolonged, and often occur in clusters.^{5,11,12,136,171} More than 50% of the patients experience early unilateral or generalized clonic or tonic–clonic status epilepticus (SE), despite adequate treatment.¹³ Two-thirds of the subjects develop, between 1 and 5 years of age,
atypical absences, often accompanied by a mild myoclonic component, mainly involving the eyelids and axorizomelic muscles.^{5,11,12,13,14,136} Such episodes are accompanied by generalized slow spike-and-wave complexes. The interictal EEG shows high-amplitude, fast spikes, polyspikes, and wave complexes over the posterior third of the head on eye closure. Other seizure types have been described in a minority of patients (Fig. 4).^80,171