Pelizaeus-Merzbacher

Basic Facts About Pelizaeus-Merzbacher Disease and Spastic Paraplegia Type 2

Pelizaeus-Merzbacher Disease (PMD) and Spastic Paraplegia Type 2 (SPG2) are part of a spectrum of disease with varying severity. There are four general classifications with this spectrum of diseases. In order of severity, these are connatal PMD, classic PMD, complicated SPG2, and pure SPG2. Symptoms of each will be discussed below.

What causes PMD and SPG2?

These diseases are caused by a defect in a gene called proteolipid protein (PLP). PLP is involved in transmitting information between cells. It is the most abundant protein present in myelin (see our general leukodystrophy fact sheet for more information on myelin), and is very important for the proper functioning of the nervous system.

How are PMD and SPG2 inherited?

PMD and SPG2 are X-linked disorders (see our fact sheet on genetic inheritance for extensive information on this). Briefly, this means that the gene responsible for the disorder (in this case, PLP) is present on the X chromosome. Women have two X chromosomes, so if one X chromosome has a defective gene, they can compensate for that because they have a good copy of that gene on their other X chromosome. However, because men only have one X chromosome, they only have one copy of each gene. If a gene is defective, they do not have another copy to compensate.

Because of this, men are much more likely to have PMD and SPG2. There are some cases of the diseases in women, but they are less frequent and generally milder forms of the disease.

 How are these disorders diagnosed?

Certain symptoms and abnormalities suggest a diagnosis of Pelizaeus-Merzbacher Disease (PMD) and Spastic Paraplegia Type 2 (SPG2).  Because the gene responsible for these disorders is known, genetic screening techniques can be used to confirm a diagnosis. In addition, these same techniques can be used for prenatal diagnosis, as well as identification of women who carry the disease and are therefore more likely to have affected children.  This allows couples to make informed decisions about having a family.

What are the symptoms of Pelizaeus-Merzbacher Disease and Spastic Paraplegia Type II?

As mentioned above, this spectrum encompasses several disorders with varying degrees of severity. These are connatal PMD, classic PMD, complicated SPG2, and pure SPG2. Each is addressed separately below.

Connatal PMD

Connatal PMD is the most severe of this spectrum of disorders. Patients show a delayed development and severe neurological symptoms. Patients may have feeding problems, difficulties with breathing, and the prominent muscle spasms often lead to difficulties in patient care. Seizures may be present. Death usually occurs within the first decade of life. Symptoms are present at birth, and may include many of the following:

  • Nystagmus: involuntary movements of the eyes
  • Hypotonia: lack of muscle tone
  • Ataxia: disturbance of gait (walking) or coordination
  • Severe spasticity: tendency to have involuntary muscle contraction
  • Stridor: a harsh vibrating sound heard during respiration when the air passage is blocked
  • Pharyngeal weakness: the pharynx is the voice box; pharyngeal weakness therefore results in speech difficulties
  • Seizures
  • Impaired cognition
  • Lack of development of speech

Classic PMD

Early symptoms include muscle weakness, involuntary movements of the eye, and delay in motor development that can be seen within the first year of life. Spastic contractions, difficulties with walking, and aimless muscle movements develop later. Despite the prominent developmental delay of motor skills, patients often show slow development in the first decade of life, and then slowly deteriorate until death in mid-adulthood.

  • Nystagmus: involuntary movements of the eyes
  • Fail to develop head control
  • Tremors of the head
  • Bradylalia: abnormal slowness or deliberation in speech
  • Ataxia: disturbance of gait (walking) or coordination
  • Choreoathetosis: a condition marked by aimless muscle movements and involuntary motinos
  • Tremor of upper limbs
  • Spastic contractions of lower limbs
  • Mild dementia
  • Dystonia: abnormal muscle tone, with sustained muscle contractions, can typically contort the limbs in an abnormal posture (such as wry neck or writer’s cramp).
  • Impaired cognition

SPG2

Patients with SPG2 show normal motor development in the first year of life, but between 2 and 1 years of age, progressive weakness and involuntary muscle contractions occur in the lower limbs. In some cases some of the symptoms of PMD occur. These tend to be less prominent in SPT2 than they are in PMD. These symptoms are listed below with definitions as necessary. In some cases, there is neurological involvement, and mental retardation may be present. Cases where there is involvement of the brain are termed “complicated” PMD, while cases of PMD that do not have neurologic complications are termed “pure” PMD.

  • Nystagmus: involuntary movements of the eyes
  • Optic atrophy: muscle wasting of the eye: this can result in vision difficulties
  • Ataxia: disturbance of gait (walking) or coordination
  • Dysarthria: difficulty pronouncing words, typically with thick or slurred speech
  • Dystonia: abnormal muscle tone, with sustained muscle contractions, can typically contort the limbs in an abnormal posture (such as wry neck or writer’s cramp).

Female heterozygotes

Female heterozygotes are women who carry one copy of the defective gene and one good copy of the gene. Because they have the good copy of the gene, these women may not show any symptoms. However, in some cases symptoms have been observed, though the particular symptoms and course of the disease are quite variable. Next we describe a few of these cases.

Female heterozygotes have been found with an early-onset but mild form of PMD or SPG2; in these cases, the symptoms have faded over time. In families that include men with the severe forms of these diseases, some of the female heterozygotes have been observed to have transient neurologic symptoms in childhood, but do not develop PMD or SPG2. Strangely, in families with men with one of the milder forms of these diseases, some of the female carriers in the family have been observed to have a late-onset form of PMD or SPG2.

What is the treatment for PMD and SPG2?

There is no treatment for PMD or SPG2; treatment is currently symptomatic and supportive. This may include medication for seizures and the stiffness or abnormal muscle contractions that are a problem for many PMD patients. 

How is scientific research on PMD and SPG2 progressing towards improvement in treatment or diagnosis?

Scientific research has led to the identification of the gene involved in PMD and SPG2. This has allowed scientists to develop better methods of diagnosing the disease, and has provided families with the option of prenatal screening and improved genetic counseling. As a result of the identification of the gene, many animal models for these diseases have been developed, and we hope that studies of these models may lead to new treatments. 

Other Clinical Names for PMD and SPG2

  • SPPX2 (note that this is specifically a term referring to SPG2)
  • Perinatal sudanophilic leukodystrophy (note that this term specifically refers to PMD)