PPM-X syndrome (MRXS13)

Evidence note: PPM-X is extremely rare. Much of the published phenotype comes from a small number of families and case reports, so features and progression should not be assumed for an individual.

PPM-X is a historical name for X-linked intellectual developmental disorder, syndromic 13 (MRXS13), also called X-linked intellectual disability–psychosis–macroorchidism syndrome or Lindsay-Burn syndrome. The name originally referred to psychosis, pyramidal signs, and macroorchidism in affected males. Current sources place PPM-X within the spectrum of disorders caused by pathogenic sequence variants in MECP2 at Xq28. It is distinct from MECP2 duplication syndrome. GeneReviews, 2025; NCBI MedGen

Quick reference

Do not use Q99.2 for PPM-X: in ICD-10-CM that code denotes fragile X chromosome (ICD-10-CM Q99.2). Confirm any ICD-10-CM or ICD-11 assignment against the official code set for the care year rather than copying a code from this page.

What is known

The syndrome was first described in a three-generation family with six affected males. All had moderate intellectual disability. Four had recurrent manic-depressive illness, and the family also showed pyramidal signs, parkinsonian features, and macroorchidism. The original linkage study mapped the disorder to Xq28; later work identified the MECP2 p.Ala140Val variant in affected males and carrier females. Lindsay et al., 1996; Klauck et al., 2002

Reports from other families show that the p.Ala140Val phenotype is variable. Intellectual disability and language impairment are common, while spasticity, hyperreflexia, gait change, tremor, parkinsonian features, and psychiatric symptoms occur in some individuals. Females with the variant may have mild learning disability or more substantial neurological and psychiatric features. Not every person has every feature in the PPM-X name. Lambert et al., 2016; Venkateswaran et al., 2014

PPM-X is not a REN-related disorder. REN encodes renin and is not the gene associated with MRXS13. PPM-X is also not caused by an extra copy of MECP2; MECP2 duplication syndrome is a separate condition with a different typical phenotype and testing result. GeneReviews, 2025

Diagnosis

Clinical features alone do not confirm PPM-X. Evaluation should be coordinated by clinical genetics and generally includes:

• a developmental, neurological, psychiatric, and three-generation family history;
• examination for tone, reflex, gait, involuntary movement, and other relevant findings;
• molecular genetic testing that can identify a pathogenic or likely pathogenic MECP2 sequence variant; and
• variant interpretation in the context of the person's phenotype and family, because MECP2 variants are associated with several distinct disorders.

Brain MRI, EEG, electromyography, or nerve-conduction studies may be selected to investigate an individual's findings or differential diagnosis, but PPM-X does not have a single diagnostic imaging pattern. GeneReviews, 2025

Genetic counseling should address X-linked inheritance, variable expression in females, testing of appropriate relatives, and reproductive options. Risk estimates must be based on the family's identified variant and parental testing rather than a generic recurrence percentage.

Communication and AAC

Published reports describe intellectual disability and impaired language development, with dysarthria in some affected people. They do not establish one communication profile or an inevitable loss of speech. Assessment should therefore be individualized and repeated when motor, psychiatric, sensory, or cognitive function changes.

An SLP and assistive-technology team should assess:

• comprehension, expressive language, speech intelligibility, literacy, and preferred communication modes;
• hearing, vision, positioning, reach, pointing accuracy, tremor, spasticity, and fatigue;
• the effect of mood, psychosis, medication, and environment on participation; and
• communication needs across home, education, health care, work, and community settings.

Support existing speech, gesture, writing, and facial expression while adding AAC when it improves reliability or participation. Options may include communication books or boards, text or symbol-based systems, speech-generating devices, and partner-assisted scanning. Select access through observed performance: direct touch or pointing when reliable, adapted switches or scanning when motor control is inconsistent, and eye-gaze access only when vision, oculomotor control, attention, and calibration support it. Provide a low-tech backup and train communication partners.

There is no evidence that every person with PPM-X requires a wheelchair, eye tracking, a feeding aid, or a particular AAC system.

Management and support

No PPM-X-specific disease-modifying treatment or management guideline was identified. Care is based on the person's manifestations and goals and may involve clinical genetics, neurology, developmental medicine, psychiatry, primary care, rehabilitation, psychology, and communication services.

• Monitor development, adaptive function, communication, mobility, and mental health.
• Evaluate new gait change, spasticity, tremor, seizures, regression, or swallowing concerns rather than assuming they are part of an expected course.
• Treat psychiatric symptoms through an appropriately qualified clinician, with accessible assessment and a reliable way for the person to report effects and adverse effects.
• Use physical and occupational therapy and adaptive equipment to address measured needs, comfort, participation, and safety.
• Include the person in decisions using their most reliable communication method.

The available literature does not support a standard sequence from early spasticity to paraplegia, universal cognitive deterioration, predictable autonomic dysfunction, or experimental treatment targeting the renin-angiotensin system.

References

1. Kaur S, Christodoulou J. MECP2 Disorders. GeneReviews. Revised December 4, 2025. NCBI Bookshelf
2. Lindsay S, et al. PPM-X: a new X-linked mental retardation syndrome with psychosis, pyramidal signs, and macroorchidism maps to Xq28. American Journal of Human Genetics. 1996;58:1120–1126. PMID 8651288 · Free full text
3. Klauck SM, et al. A mutation hot spot for nonspecific X-linked mental retardation in the MECP2 gene causes the PPM-X syndrome. American Journal of Human Genetics. 2002;70:1034–1037. PMID 11885030 · Free full text · DOI 10.1086/339553
4. Lambert S, et al. Expanding phenotype of p.Ala140Val mutation in MECP2 in a 4 generation family with X-linked intellectual disability and spasticity. European Journal of Medical Genetics. 2016;59:522–525. PMID 27465203 · DOI 10.1016/j.ejmg.2016.07.003
5. Venkateswaran S. Adolescent onset cognitive regression and neuropsychiatric symptoms associated with the A140V MECP2 mutation. Developmental Medicine & Child Neurology. 2014;56:91–94. DOI 10.1111/dmcn.12334
6. NCBI MedGen. X-linked intellectual disability–psychosis–macroorchidism syndrome (MRXS13). C0796222