As mentioned earlier, different Pelizaeus-Merzbacher disease forms extend over a clinical spectrum of varying severity. However, there are general clinical features that are found in all forms, including nystagmus, delayed milestones, and spasticity. According to a case series study conducted in Colombia on PMD male patients aged six months to 16 years, 57% had horizontal nystagmus, and 43% had rotatory nystagmus. Moreover, 71.4% had cerebellar signs, and 85.7% were spastic.[7] In the coming lines, the clinical features of each form of PMD will be described in detail.

Seitelberger classified the PMD forms at the severe end of the spectrum into three types with type I or the connatal form being the most severe and type III or the classic form being relatively the mildest. Type II, or the transitional type, falls in between the others.[4] Both connatal and classic PMD present with titubation and significant initial hypotonia, which later converts to spasticity. Moreover, both types of patients are ataxic and have nystagmus, which can be either horizontal or vertical with fast and irregular oscillations.

Patients with classic PMD, who present with the disease at around 1 year of age, become eventually spastic but retain the ability to ambulate partially and their cognition, though impaired, is preserved to a certain degree with the production of speech. On the other hand, connatal patients present with the disease as soon as they are born, cannot ambulate or speak, and their cognition is significantly impaired. They also typically present with laryngeal stridor and pharyngeal weakness, which some of them succumb to early in life.[4][2] If proper care is administered, survival can be extended up to the third decade. According to a case report from the Czech Republic, a boy with connatal PMD died at the age of 13 years due to respiratory failure.[8] Patients with classic PMD can exhibit athetosis and can survive up to 70 years.

Coming to the milder end of the spectrum of PMD, spastic paraplegia type 2 (SPG2) presents later than types I, II, and III PMD described above. It is classified into complicated and uncomplicated or pure. Complicated SPG2 presents with autonomic disturbances, including bladder spasticity, ataxia, spastic paraparesis, nystagmus, and some degree of cognitive impairment. It is associated with HEMS (hypomyelination of early myelinating structures). Uncomplicated SPG2, on the other hand, presents with bladder spasticity and spastic paraparesis. Both types of SPG2 patients have a normal life expectancy.[9][2]

PLP1 null syndrome presents with the unique feature of peripheral neuropathy that distinguishes it from the rest of the PMD disorders. Patients have a normal life expectancy and tend to have mild spastic paraplegia and cognitive impairment. As time progresses, their motor functions continue to decline.[9][1]

Imaging is very crucial in supporting the diagnosis of Pelizaeus-Merzbacher disease. Being a hypomyelinating disorder, PMD’s detrimental effects on myelin formation can be seen with computed tomography (CT) and magnetic resonance imaging (MRI), with MRI being more accurate. CT reveals white matter attenuation and progressive atrophy similar to other leukodystrophies. MRI shows significant hypomyelination and can distinguish between the connatal and SPG2 forms of PMD. Normally, myelin maturation translates to an increase in T1 MRI signaling and a decrease in T2 signaling. However, in patients of PMD, maturation fails, and hyperintensities are seen on T2. The hyperintensities are seen diffusely in patients with connatal PMD and a patchy manner in SPG2 patients over various areas of the brain, including posterior limb of the internal capsule, optical radiations, and corona radiata. Patients with connatal PMD can also have cerebellar hypoplasia. According to Sumida et al., a cohort study of 19 patients that the diffuse nature of T2-hyperintensity correlates with PMD severity.[4][10]

A case report from Brazil suggests that if an MRI shows pontine demyelination in a patient exhibiting clinical features of PMD, another diagnosis should be kept in mind: Pelizaeus-Merzbacher-like disease (PMLD). PMLD is a disease similar to PMD but with different etiology, the details of which will be explained in the differential diagnosis section. [11]

Molecular analysis remains the mainstay in confirming the diagnosis of PMD. It includes methods like fluorescence in-situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) methods and chromosomal microarray testing, with the latter being most efficient in detecting duplication mutations and their extent. According to a molecular analysis study in Poland involving 68 patients, duplications leading to increased production of PLP1 gene and its accompanying protein DM20 were found along with other missense and nonsense mutations leading to premature termination of PLP1 synthesis.[12][13]

A recent study from Japan proves the efficacy of droplet-digital polymerase chain reaction (dd-PCR) in detecting PLP1 mutations and suggested that it can be used in routine clinical practice as an alternative option to the conventional ones.[12]

Finally, neurophysiology plays a minor role in supporting the diagnosis of PMD. Brain auditory-evoked responses and somatosensory evoked potentials are abnormal in PMD along with nerve conduction studies, which show evidence of peripheral neuropathy in cases of PLP1 null syndrome.[4]

There is no definitive treatment for Pelizaeus-Merzbacher disease; it is mainly symptomatic and palliative. However, studies are taking place to investigate treatments that target the molecular mechanisms responsible for PMD.

Patients with connatal PMD have seizures that are usually responsive to antiepileptic medications (AED). Currently, there is no AED that is used specifically to treat seizures due to PMD. Spasticity is a major symptom in PMD, and centrally-acting skeletal muscle relaxants such as baclofen, tizanidine, or diazepam are effective in treating it. Due to pharyngeal weakness that some patients of PMD experience, a gastrostomy is done, and enteral feeding is initiated. A lot of PMD patients experience some degree of scoliosis, which necessitates physiotherapy and/or surgery.[14]

Studies on some drugs yielded promising results in targeting the molecular cause of PMD. However, they have been mostly tested on genetically modified mice (mutated PLP1) and not in humans. Lonaprisan, a progesterone receptor antagonist, decreases PLP1 overexpression caused by the mutation; therefore, it increases myelination. According to Epplen et al., curcumin, an extract of turmeric, has been correlated with motor improvement and decreased oligodendrocyte loss in mice with PLP1 overexpression. It works by exerting an anti-oxidative effect promoting axonal survival and reducing the inflammatory process that occurs in PMD.[4]

Dietary changes can also exert an effect on the pathophysiology of the disease. A diet rich in cholesterol can increase the life span of oligodendrocytes and the axonal caliber, according to a study conducted by Rudolphi et al.[4] Stumpf et al. demonstrated that ketogenic diet, which is high in fat and low in carbohydrates, is capable of restoring oligodendrocytes; hence, leading to increased CNS myelination in mutant mice having overexpression of PLP1. Ketone bodies produced as a result of this diet readily cross the blood-brain barrier and provide the building blocks for CNS lipid synthesis.[15]

Pelizaeus-Merzbacher disease belongs to leukodystrophies, which present with overlapping clinical findings. Therefore, most of the leukodystrophies should be considered and ruled out prior to confirming the diagnosis of PMD. In general, all leukodystrophies present with a progressive neurological decline, including motor and cognitive. They can categorize into lysosomal abnormalities like metachromatic leukodystrophy, peroxisomal defects like adrenoleukodystrophy, mitochondrial disorders, and disorders of myelin synthesis like PMD and PMLD.[16] Leukodystrophies differ in their mode of transmission, genetic basis, and clinical presentation.

It is important to describe PMLD in detail, given the significant similarities with PMD. Initially thought to be PMD, PMLD is due to a mutation at the level of the GJC2 gene. It is an autosomal recessive disorder; hence, the individual can get affected regardless of sex. Moreover, though both PMD and PMLD exhibit hypomyelination on MRI, brainstem involvement, especially the pons, is seen more frequently in PMLD.[17]

The milder side of the spectrum of PMD disorders includes SPG2, as discussed above. Therefore, the list of spastic paraplegias should be considered as differential diagnoses. According to a clinical review by Finsterer et al., there are 52 types of SPG. All SPGs present with spasticity and several other overlapping features. However, each has distinctive features; of note, SPG1 or MASA syndrome presents with mental retardation, hydrocephalus, and aphasia and is due to a mutation at the level of the L1CAM gene. SPG2, a subtype of PMD, is differentiated from other SPGs by molecular analysis that reveals a mutation at the PLP1 gene.[18]

The prognosis of patients with Pelizaeus-Merzbacher disease disorders varies over the spectrum. Patients with connatal forms usually live until childhood. Some of them die very early due to respiratory complications. Proper care can extend their lives up to the third decade. Patients of classic PMD survive longer up to the seventh decade. On the other hand, patients on the mild end of the spectrum (SPG2 and null syndrome) have a near-normal life expectancy.[4][2]

Patients with Pelizaeus-Merzbacher disease, particularly the severe types, do have a significant number of complications that increase both morbidity and mortality. According to a report by Golomb et al., about 11 patients with symptoms of PMD, perinatal complications like meconium aspiration, and pneumothorax have occurred requiring rehabilitation in the form of tracheostomy and compression machine at the age of 10 months. Besides, there were feeding problems which required gastrostomy. Other complications include scoliosis and sleep disturbances, which were responsive to melatonin.[19]

Early intervention in patients with PMD can prevent complications and further neurologic deterioration. According to a case report by Jang et al., a patient received neuro-developmental training to improve balance and developmental delay. The results were promising as the child showed improvement in his motor functions. This emphasizes the importance of training to prevent complications in the long run.[20]

Genetic counseling is the mainstay of educating patients regarding the spectrum of PMD disorders. Families should be informed about the nature of the disease, modes of transmission, and dealing with complications. This would help them make informed decisions based on clinical grounds. Besides, a genetic risk assessment should be conducted.[9]

Given the fact the Pelizaeus-Merzbacher disease is a multifaceted disease, a collaboration of different members from the interprofessional team is needed to administer the best care possible to patients of PMD. This would involve a neurologist as the CNS is the primary target of PMD, a pulmonologist given the stridor and respiratory difficulties that might occur in some patients of PMD, a gastroenterologist because of the pharyngeal weakness leading to feeding difficulties, physiotherapist to ease breathing in cases of contractures and scoliosis, a geneticist to counsel families with PMD.[14][9]

Treatment options for PMD are under investigation. A study conducted by Gruenenfelder et al. explores the role of stem cell transplantation in PMD. The study used genetically modified mice with a duplication mutation at PLP1, and it concluded that the injection of neural stem cells had the potential to restore the production of myelin and protect axons.[21] Umbilical cord blood transplantation (UCBT) proved to be beneficial in treating patients of PMD, according to a case report published by Wishnew et al. In the report, two young boys having a confirmed diagnosis of PMD were referred to UCBT consultation as a potential treatment. The results of UCBT were promising- at 1-year and 7-year follow-ups, the MRI of both the boys showed myelination. The boys showed marked acquisition of cognition with mild improvement in motor skills.[22]

A clinical trial by Gupta et al. demonstrated good results of intracerebral injection of neural stem cells in 2 subjects of PMD. The results were consistent with remyelination. The first subject, though, did not have significant neurologic improvement, experienced an improvement in his continuous positive airway pressure support (recall that patients with severe PMD have stridor). The second subject had improved truncal support, ambulation, and speech.[23]

Apart from potential treatments, a recent study by Cloake et al. shows that PLP1 mutations might be related to the pathophysiology in multiple sclerosis (MS) patients. The genes of 42 female patients MS were sequenced, and it was found out they have mutations of PLP1. This concludes that myelin-producing genes could contribute to MS pathology, given the destruction of oligodendrocytes that occurs as a result of the mutation.[24]