Overview
In this section there is some scientific background of basic genetics and MASNS.
Our bodies are made up of trillions of cells. Within each cell is a nucleus, which contains X-shaped structures called chromosomes. Human body cells normally have 46 chromosomes. Pairs of human chromosomes numbered from 1 through 22 are called autosomes and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes.
These chromosomes are made up of tightly wound strands of DNA, our genetic material. Segments of DNA that provide instructions for the body to make proteins are called genes. Proteins play a critical role in many functions of the body. When a change (mutation) in a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain. The gene that is altered in patients with MASNS is the PRKAR1B gene, located on the short (p) arm of chromosome 7chromosome 7 (7p22).
Inheritance Pattern
Most genetic diseases are determined by the status of the two copies of a gene, one received from the father and one from the mother.
The inheritance pattern of the disease caused by PRKAR1B mutations is autosomal dominant, which means that only a single abnormal copy of the gene is necessary to cause the disease. Mutations in PRKAR1B can either be gene deletions, meaning the entire gene is missing, or point mutations, meaning just one letter in the DNA code is changed. The diagnosis of PRKAR1B mutations takes place through either whole exome sequencing or chromosome microarray analysis (CMA).
Abnormal genes can either be inherited from a parent, or can result from de novo mutations, meaning that the parents are unaffected and the mutation arose spontaneously during the development of the parents’ sperm and egg cells. As of today, all documented cases of MASNS are considered de novo mutations.
Underlying Pathophysiological Mechanism
The PRKAR1B gene encodes the regulatory subunit RI-beta of the cyclic AMP (cAMP)-dependent protein kinase A (PKA) complex. PKA is an essential enzyme in the signaling pathway of the second messenger cAMP. Through phosphorylation of target proteins, PKA controls many biochemical events in the cell including regulation of metabolism, ion transport, and gene transcription. The PKA heterotetramer is composed of 2 regulatory and 2 catalytic subunits (summary by Solberg et al., 1992). While PKA complexes are present in all human tissues, the respective composition of PKA varies across cell types, depending on the expression of different subunits. 
In humans there are 4 different regulatory subunits: R1α, R1β, R2α and R2β, and 6 principal catalytic subunits. Regulatory subunits mediate the localization of PKA to a cellular compartment by binding A-kinase-anchoring proteins (AKAPs; Pidoux & Tasken, 2010; Taylor, Keshwani et al., 2012b), and PKA kinase activity by releasing catalytic subunits in the presence of cAMP (Soberg & Skalhegg, 2018; Taylor, Ilouz et al., 2012a).
The subunit RIβ is primarily expressed in the brain (Cadd & McKnight 1989; Uhlen et al., 2015) with the highest levels of expression in the cerebral cortex and hypothalamus (Sjöstedt et al., 2020)
While molecular and cellular disease mechanisms of MASNS are still unclear, the majority of patients with MASNS carry the recurring c.1003C>T missense variant. On the molecular level, the variant leads to the substitution of an arginine residue by a tryptophan residue within one of the two cAMP-binding domains of R1β (Ilouz et al., 2012), which might impair the cAMP-sensing property of the mutant protein. If this holds true, PKA complexes containing mutant R1β would be less sensitive to rising cAMP concentrations, affecting cellular signaling downstream of PKA in PRKAR1B-expressing cells of the CNS.
This theory would be consistent with the observation of a reduced PKA activity in cell lines harbouring mutations compared to controls (Marbach et al., 2021).