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Page 283 Jyonouchi. J Transl Genet Genom 2023;7:274-90 https://dx.doi.org/10.20517/jtgg.2023.32

are inherited in an AD pattern, despite the recent identification of APDS, the frequency of this condition is
expected to be fairly high; a total of 243 APDS patients were reported in the systemic review published in
[89]
2020 . We already follow two APDS patients in our clinic and it is not unusual for these patients to be
found in other immunology clinics.

PI3Kδ coded by PIK3CD is upregulated in developing brains, and developmental delay and ASD-like
[89]
behavioral symptoms have been described in APDS patients, more commonly in APDS2 patients .
Neurodevelopmental delay may manifest as mild cognitive impairment and/or learning disabilities .
[90]

The variable clinical manifestations of APDS led to highly individualized treatments for controlling the
affected areas. Impaired humoral and cellular immunity are treated with Ig replacement therapy and
prophylactic antibiosis targeting intracellular organisms. When they develop autoimmune complications,
immunosuppressive treatment is often required. In addition to the 1st line of treatment measures such as
steroids, therapies targeting the PI3Kδ signaling pathway have been tried. Sirolimus, a mTOR inhibitor, has
[91]
been used, because sirolimus blocks mTOR, a gatekeeper enzyme, downstream of PI3Kδ . Oral agents that
directly inhibit enzymatic actions of PI3Kδ are now available with promising results [92,93] . These PI3Kδ
inhibitors have also been used for treating malignancies such as CLL (chronic lymphocytic leukemia).
However, it remains to be seen if these oral medications are applicable for controlling the CNS
inflammation associated with dysregulated activation of PI3Kδ.

(2) PTEN hamartoma tumor syndrome (PHTS): PTEN (phosphatase and tensin homolog) coded by PTEN
serves as an antagonist of PI3K/Akt/mTOR pathway activation. PTEN suppresses activation of this pathway
by hydrolyzing PIP3 to PIP2, thereby inhibiting secondary messenger actions of PIP3 generated by
PI3Kδ . With this action, PTEN serves as a tumor suppressor, and heterozygous germline mutations of
[94]
[95]
PTEN are associated with cancer syndromes . Although PHTS is considered to be rare, previously
described under multiple names of syndromes, the development of comprehensive diagnostic guidelines
[96]
will provide better information on true prevalence . Inherited LOF, AD, PTEN variants that result in over-
activation of the PI3K/Akt/mTOR pathway will cause clinical features resembling those seen in APDS,
which is referred to as APDS-like syndrome [85,96] . As with APDS patients, impaired neurodevelopment is also
expected to occur in PHTS patients. In fact, a subset of PHTS patients are known to exhibit clinical features
overlapping with ASD (impaired speech/social skills, and repetitive behaviors) along with macrocephaly
[94]
and a high frequency of seizures . It has been reported that PTEN mutations associated with ASD-like
clinical features are dominant negative mutations, causing unstable but functional protein products,
[94]
indicating the importance of PTEN in the early stage of neuronal development . In MIA models in which
maternal inflammation is induced by a low dose of endotoxin during pregnancy, mice carrying LOF PTEN
variants revealed worsening macrocephalus and ASD-like behavioral symptoms in offspring . Several
[97]
PTEN animal models have also been shown to exhibit ASD-like clinical features . Overactivation of PI3K/
[98]
Akt/mTOR pathways due to PETN mutations will cause dysregulated immune activation and subsequent
[85]
neuroinflammation and autoimmune conditions . Therefore, PHTS subjects will be a good candidate for
blockers targeting PI3K/Akt/mTOR pathways.

Sirolimus, an inhibitor of mTORC1, has been shown to attenuate clinical symptoms of PHTS patients [98,99] .
A 6 month, randomized, double-blinded, placebo-controlled clinical trial of everolimus, another mTORC1
inhibitor, was recently conducted to evaluate its effects on neurocognitive symptoms in PHTS patients. The
results indicated that everolimus has modest effects, but the wide range of ages in the study subjects
[100]
(5-45 years) may have masked its therapeutic effects . As seen in APDS patients, inhibitors of AKT and
PIK3CA may also be applicable for treating PHTS, but these agents are not commercially available at this
[99]
time .