Tag Archives: #musculardystrophy

Muscular Dystrophy – Charcot Marie Tooth

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Background:  We are working with a family here in the United States and in Europe in an attempt to help identify the familial gene for Charcot-Marie-Tooth Disease (CMT) so that the daughters can attempt IVF with Preimplantation Genetic Diagnosis (PGD).

Analysis:  Charcot-Marie-Tooth Disease (CMT) is one of the most common hereditary motor and sensory neuropathies. The condition was named after Jean Martin Charcot and Pierre Marie in Paris and Howard Henry Tooth in Cambridge, England, who first described the condition in 1886.

The incidence of Charcot-Marie-Tooth is approximately 1 in 2500 in the United States although it varies regionally being 1 in 1214 in Norway and 1 in 6500 in the United Kingdom. 

At least 14 types of CMT disease have been described:

  • 7 inherited in an autosomal dominant manner
  • 3 in an autosomal recessive manner
  • 4 types that are inherited in a sex (X) linked recessive manner.

The most common mode of inheritance is autosomal dominant in which only one deleterious (disease causing) mutation can result in the disease affecting 1:2 (50%) of children, male or female inheriting the disease causing mutation from one affected parent. One of the common characteristics of an autosomal dominantly inherited condition is variable expression in which the severity of the presenting symptoms may vary considerably.

CMT Type 1:

  • Believed to be inherited in an autosomal dominant manner, sex (X) linked dominant inheritance and less commonly sporadic (de novo) mutations have also been reported. The various types of CMT have been divided into subtypes based on the known causative mutations and their chromosomal locations.

Autosomal Recessive Inheritance of Charcot-Marie-Tooth Disease requires the inheritance of one deleterious gene from each unaffected carrier parent. The disease is often earlier in onset and more severe. 25% (1 in 4) children will be affected, 25% (1 in 4) children will inherit only the normal unaffected allele and be unaffected and non-carrier and 50% (1 in 2) will inherit one deleterious gene from only one parent and be an unaffected carrier like each parent. Male and female children are equal risk.

Sex (X) Linked Recessive Inheritance is caused when an unaffected carrier mother passes a deleterious mutation on one X chromosome to a child. Affected males having only one X chromosome will pass the affected X to all female children who will be “unaffected” carriers or usually have milder disease. Male children from an affected father will receive their father’s Y chromosome and be unaffected. Carrier females will have a 50% (1 in 2) risk of passing their deleterious X chromosome to each male child. Female children have a 50% (1 in 2) risk of inheriting the deleterious X chromosome and be a carrier female like their mother.

Symptoms often include:

  • Weakness and sensory loss in arms and legs
  • Numbness in the feet
  • Depressed tendon reflexes
  • High foot arches or hammer toes
  • Ultimate muscle weakness and wasting
  • Decreased sensation in hands and feet
  • Increased tendency toward injury which may go unnoticed.

The diagnosis is often made clinically. However, multiple DNA gene panels are available including analyzing peripheral blood for 17 genes, 45 genes or 82 genes depending on the likely mode of inheritance including causative genes and several preliminary evidence genes.

Rarely the same disorder or a similar disorder (phenocopy) can result from a different cause and involve other genes.

Charcot Marie Tooth

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Background:  We are working with a family here in the United States and in Europe in an attempt to help identify the familial gene for Charcot-Marie-Tooth Disease (CMT) so that the daughters can attempt IVF with Preimplantation Genetic Diagnosis (PGD).

Analysis:  Charcot-Marie-Tooth Disease (CMT) is one of the most common hereditary motor and sensory neuropathies. The condition was named after Jean Martin Charcot and Pierre Marie in Paris and Howard Henry Tooth in Cambridge, England, who first described the condition in 1886.

The incidence of Charcot-Marie-Tooth is approximately 1 in 2500 in the United States although it varies regionally being 1 in 1214 in Norway and 1 in 6500 in the United Kingdom. 

At least 14 types of CMT disease have been described:

  • 7 inherited in an autosomal dominant manner
  • 3 in an autosomal recessive manner
  • 4 types that are inherited in a sex (X) linked recessive manner.

The most common mode of inheritance is autosomal dominant in which only one deleterious (disease causing) mutation can result in the disease affecting 1:2 (50%) of children, male or female inheriting the disease causing mutation from one affected parent. One of the common characteristics of an autosomal dominantly inherited condition is variable expression in which the severity of the presenting symptoms may vary considerably.

CMT Type 1:

  • Believed to be inherited in an autosomal dominant manner, sex (X) linked dominant inheritance and less commonly sporadic (de novo) mutations have also been reported. The various types of CMT have been divided into subtypes based on the known causative mutations and their chromosomal locations.

Autosomal Recessive Inheritance of Charcot-Marie-Tooth Disease requires the inheritance of one deleterious gene from each unaffected carrier parent. The disease is often earlier in onset and more severe. 25% (1 in 4) children will be affected, 25% (1 in 4) children will inherit only the normal unaffected allele and be unaffected and non-carrier and 50% (1 in 2) will inherit one deleterious gene from only one parent and be an unaffected carrier like each parent. Male and female children are equal risk.

Sex (X) Linked Recessive Inheritance is caused when an unaffected carrier mother passes a deleterious mutation on one X chromosome to a child. Affected males having only one X chromosome will pass the affected X to all female children who will be “unaffected” carriers or usually have milder disease. Male children from an affected father will receive their father’s Y chromosome and be unaffected. Carrier females will have a 50% (1 in 2) risk of passing their deleterious X chromosome to each male child. Female children have a 50% (1 in 2) risk of inheriting the deleterious X chromosome and be a carrier female like their mother.

Symptoms often include:

  • Weakness and sensory loss in arms and legs
  • Numbness in the feet
  • Depressed tendon reflexes
  • High foot arches or hammer toes
  • Ultimate muscle weakness and wasting
  • Decreased sensation in hands and feet
  • Increased tendency toward injury which may go unnoticed.

The diagnosis is often made clinically. However, multiple DNA gene panels are available including analyzing peripheral blood for 17 genes, 45 genes or 82 genes depending on the likely mode of inheritance including causative genes and several preliminary evidence genes.

Rarely the same disorder or a similar disorder (phenocopy) can result from a different cause and involve other genes.

Reproductive Medicine – Charcot Marie Tooth

© 2018, GENASSIST, Inc.

By Keith S. Wexler, MBA, CFO, Business Development Director GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Background:  We are working with a family here in the United States and in Europe in an attempt to help identify the familial gene for Charcot-Marie-Tooth Disease (CMT) so that the daughters can attempt IVF with Preimplantation Genetic Diagnosis (PGD).

Analysis:  Charcot-Marie-Tooth Disease (CMT) is one of the most common hereditary motor and sensory neuropathies. The condition was named after Jean Martin Charcot and Pierre Marie in Paris and Howard Henry Tooth in Cambridge, England, who first described the condition in 1886.

The incidence of Charcot-Marie-Tooth is approximately 1 in 2500 in the United States although it varies regionally being 1 in 1214 in Norway and 1 in 6500 in the United Kingdom. 

At least 14 types of CMT disease have been described:

  • 7 inherited in an autosomal dominant manner
  • 3 in an autosomal recessive manner
  • 4 types that are inherited in a sex (X) linked recessive manner.

The most common mode of inheritance is autosomal dominant in which only one deleterious (disease causing) mutation can result in the disease affecting 1:2 (50%) of children, male or female inheriting the disease causing mutation from one affected parent.

One of the common characteristics of an autosomal dominantly inherited condition is variable expression in which the severity of the presenting symptoms may vary considerably.

CMT Type 1:

  •  Believed to be inherited in an autosomal dominant manner, sex (X) linked dominant inheritance and less commonly sporadic (de novo) mutations have also been reported. The various types of CMT have been divided into subtypes based on the known causative mutations and their chromosomal locations.

Autosomal Recessive Inheritance of Charcot-Marie-Tooth Disease requires the inheritance of one deleterious gene from each unaffected carrier parent. The disease is often earlier in onset and more severe. 25% (1 in 4) children will be affected, 25% (1 in 4) children will inherit only the normal unaffected allele and be unaffected and non-carrier and 50% (1 in 2) will inherit one deleterious gene from only one parent and be an unaffected carrier like each parent. Male and female children are equal risk.

Sex (X) Linked Recessive Inheritance is caused when an unaffected carrier mother passes a deleterious mutation on one X chromosome to a child. Affected males having only one X chromosome will pass the affected X to all female children who will be “unaffected” carriers or usually have milder disease. Male children from an affected father will receive their father’s Y chromosome and be unaffected. Carrier females will have a 50% (1 in 2) risk of passing their deleterious X chromosome to each male child. Female children have a 50% (1 in 2) risk of inheriting the deleterious X chromosome and be a carrier female like their mother.

Symptoms often include:

  • Weakness and sensory loss in arms and legs
  • Numbness in the feet
  • Depressed tendon reflexes
  • High foot arches or hammer toes
  • Ultimate muscle weakness and wasting
  • Decreased sensation in hands and feet
  • Increased tendency toward injury which may go unnoticed.

The diagnosis is often made clinically. However, multiple DNA gene panels are available including analyzing peripheral blood for 17 genes, 45 genes or 82 genes depending on the likely mode of inheritance including causative genes and several preliminary evidence genes.

Rarely the same disorder or a similar disorder (phenocopy) can result from a different cause and involve other genes. 

Muscular Dystrophy – Adrenoleukodystrophy

© 2018, GENASSIST, Inc.  

By Keith S. Wexler, MBA, Maternal Fetal Medicine, Prenatal Diagnosis and Biotech/Life Sciences Consultant, GENASSIST, Inc.

Paul Wexler, M.D., F.A.C.O.G., Medical Director, GENASSIST, Inc.

Clinical Professor, Department of OB/GYN, University of Colorado Health Sciences Center

Clinical Professor, Division of Genetics/Dept. of Pediatrics, Univ. of Colorado/The Children’s Hospital

Adrenoleukodystrophy (ALD) is an X-linked fatal disease that affects the brain’s nerve cells and the adrenal glands with an incidence of approximately 1:20,000 to 1:50,000.  Severity can vary in family members.

Since ALD is an X-linked Disease: 50% of males will be affected if they inherit the carrier X chromosome from a carrier mother, 50% of females would be carriers. Some females can exhibit symptoms but they usually occur later and are milder. Most affected females inherit their X chromosome from a father with the disease.

There are three major types of Adrenoleukodystrophy (ALD):

Childhood ALD: Onset age 4 to 10 years. Symptoms: Learning problems, behavioral problems, aggression, vision problems, difficulty with coordination and swallowing and decreased adrenal function. Life expectancy: Variable, usually 1-10 years.

Adrenomyeloneuropathy: Onset age young adult to middle age (usually 20- to 35 years of age) . Symptoms: Stiffness and weakness in legs, urinary and/or genital function problems, changes in thinking and behavior and usually changes in adrenal cortex function. Life expectancy is average.

Addison Disease Only – Hypoadrenocorticism (Mildest Form): Onset age childhood to adulthood. Symptoms: Adrenal cortex insufficiency. Usually adrenomyeloneuropathy by middle age.

http://www.stopald.org/what-is-ald/

Over 600 mutations in the ABCD-1 (ATP-Binding Cassette Transporter) gene which directs the formation of the adrenoleukodystrophy protein (ALDP) and is located in eroxisomes on the long arm of the X chromosome (Xq28) causes an increase in the very long chain fatty acids (VLCFA) in the body, primarily in the brain and adrenal cortex, which is toxic to the adrenal cortex and causes an inflammatory response to myelin.

The prognosis for patients diagnosed with ALD is very variable.

Childhood ALD is progressive with life expectancy usually 1 to 10 years.

Chemotherapy and bone marrow transplantation has been tried and a new gene therapy PRCN-323 using an adeno-associated virus which is injected into the spinal fluid is in trials.

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