Genetics

• MTHFR is a rare genetic defect that can lead to complications in pregnancy.  The official name of this gene is “5,10-methylenetetrahydrofolate reductase (NADPH)”, denoted simply by MTHFR.  This gene, located on chromosome 1 at 1p36.3, produces an enzyme also called methylenetetrahydrofolate reductase.  Carriers of this genetic mutation present with hyperhomocytenemia.
• When the body is deficient in methylenetetrahydrofolate reductase, its ability to absorb folate is inhibited.  Folic acid and B9 are both essential to the development and health of the fetus.
• At least 24 mutations in the MTHFR gene have been identified in people with homocystinuria.  Most of these mutations change a single amino acid in methyl-enetetrahydrofolate reductase.  These mutations disrupt enzyme function or may inactivate it completely.
• A specific variant of the MTHFR gene may increase the risk of cardiovascular disease and birth defects.  This variant replaces the nucleotide cytosine with the nucleotide thymine at position 677 in theMTHFR gene (denoted as C677T).  This mutation is considered a risk for spina bifida and vascular disease.

Symptoms/Characteristics

• Because MTHFR is a blood-based disease with many varieties, symptoms vary depending on the exact mutation of the disease. They can include:
  • Blood clots
  • Depression
  • Anxiety
• Elevated levels of homocysteine have been associated with:
  • Placental disease
  • Preeclampsia
  • Recurrent pregnancy loss

Clinical Management
Taking folic acid can help women with certain variations of the disease.

Genetics
Niemann-Pick Types A and B (NPA and NPB) are caused by a mutation in the SMPD1 gene, leading to a deficiency of the enzyme, acid sphingomyelinase (ASM), which is required to metabolize the lipid sphingomyelin.  If ASM is absent or not functioning properly, sphingomyelin cannot be metabolized properly and is accumulated within the cell, eventually causing cell death and the malfunction of major organ systems.  Niemann-Pick Type C (NPC) is caused by a mutation in the NPC1 or NPC2 gene on chromosome 18 located at 18q11-q12.  Niemann Pick Type C patients are not able to metabolize cholesterol and other lipids properly within the cell.  All forms of Niemann-Pick are inherited in an autosomal recessive manner.

Incidence

• Types A and B affect approximately 1 in 40,000 in the Ashkenazi population
• Type C is very rare, represented by the 500 cases diagnosed worldwide

Symptoms/Characteristics

Type A Niemann-Pick disease begins during infancy and is characterized by:

• An enlarged liver and spleen (hepatosplenomegaly)
• Failure to thrive
• Progressive deterioration of the nervous system.
• Children affected by this condition generally do not survive past early childhood.
• Type A Niemann-Pick disease occurs more frequently among individuals of Ashkenazi Jewish descent

Type B disease may include signs of:

• Hepatosplenomegaly
• Growth retardation
• Problems with lung function (including frequent lung infections)
• Blood abnormalities such as abnormal cholesterol and lipid levels
• Thrombocytopenia
• Individuals affected by this type of Niemann-Pick disease usually survive into adulthood
• Type B Niemann-Pick disease occurs in all populations

Type C disease has a wide clinical spectrum and a variable age of onset. Classically, children with NPC demonstrate:

• Neurological dysfunction with cerebellar ataxia
• Dysarthria
• Seizures
• Vertical gaze palsy
• Motor impairment
• Dysphagia (difficulty in swallowing)
• Psychotic episodes
• Progressive dementia
• NPC is always fatal- the vast majority of children die before age 20

Clinical Management
There is no standard treatment that has proven to be effective for everyone, however supportive care may include involvement of specialists in gastroenterology, nutrition, physical and/or occupational therapy.  Standard medications used to treat seizures, cataplexy (sudden loss of muscle strength), dystonia (abnormal movements due to incessant muscle contractions) and spasticity can be used in NPC patients.

Del(12)(p11) or (p11p13) or t(12)(p11)
Deletions and rearrangements involving the short arm of chromosome 12 are observed in a wide variety of neoplastic and preneoplastic disease.  These include secondary acute nonlymphocytic leukemia (ANLL), specifically secondary AML and acute lymphocytic leukemia (ALL:FAB-L1).

+21
Trisomy or chromosome 21 has been observed in a wide variety of myeloid and lymphoid diseases including leukemia and myelodysplastic syndrome and occasionally in benign, leukemoid reactions in newborns.  Trisomy 21 is usually seen as a secondary chromosome change particularly in association with the blastic phase of chronic myelogenous leukemia (CML).

-Y
Loss of the Y chromosome in bone marrow is relatively common in elderly males and in most cases has to be accepted as a normal age-related phenomenon without pathogenetic significance; however, -Y has occasionally been described as a neoplastic aberration disappearing in remission and reappearing in relapse and sometimes  is the only karyotypic abnormality detectable.  Loss of the Y has been observed as a secondary change particularly, in ANLL ME patients with t(8;21) as the primary rearrangement.

i(17q)
The i(17q) has been described in ALL and is usually associated with other chromosome changes.  It is frequently observed as a secondary change in t(9;22) CML either prior to, or during a blastic phase.

Genetics
Patau syndrome, also known as trisomy 13, is a syndrome in which a patient has an additional chromosome 13 due to a non-disjunction of chromosomes during meiosis. Some are caused by Robertsonian translocations. The extra chromosome 13 disrupts the normal course of development, causing the characteristic features of Patau syndrome. Like all non-disjunction diseases (Down syndrome, Edwards syndrome, etc.), the risk of disease in the offspring increases with maternal age at pregnancy.

Incidence
Patau syndrome affects approximately 1 in 12,000 live births.

Symptoms/Characteristics

• Mental & motor retardation
• Polydactyly (extra digits)
• Holoprosencephaly (failure of the forebrain to divide properly).
• Heart defects
• Structural eye defects, including microphthalmia, Peters anomaly, cataract, iris and/or fundus (coloboma), retinal dysplasia or retinal detachment, sensory nystagmus, cortical visual loss, and optic nerve hypoplasia
• Meningomyelocele (a spinal defect)
• Omphalocele (abdominal defect)
• Abnormal genitalia
• Abnormal palm pattern
• Overlapping of fingers over thumb.
• Cutis aplasia (missing portion of the skin/hair)
• Prominent heel

Facial Features

• Microcephaly
• Low-set ears
• Cleft palate or hare lip

Clinical Management
Medical management of children with Trisomy 13 is planned on a case-by-case basis and depends on the individual circumstances of the patient. Many infants have difficulty surviving the first few days or weeks due to severe neurological problems or complex heart defects. Surgery may be necessary to repair heart defects or cleft lip and cleft palate. Physical, occupational, and speech therapy will help individuals with Patau syndrome reach their full developmental potential.

Del(20)(q11.2q13.3)
Deletions of the chromosome 20 long arm (20q) are most often observed in acute nonlymphocytic leukemia (ANLL), and myelodysplasic and myeloproliferative diseases, specifically polycythemia vera.  Additional chromosome changes such as trisomy 8 and 9, rearrangements of the chromosome 1 long arm and deleted 13q are also observed and are associated with transformation to acute leukemia.