Clinical Guidance

With respect to validated pathogenic variants in SAMD9L, no genotype-phenotype correlations have been observed.

Source: GeneReviews — "SAMD9L Ataxia-Pancytopenia Syndrome"

Penetrance

Given the variable expressivity of both hematologic and neurologic manifestations, the sometimes episodic asymptomatic cytopenias, the paucity of detailed neurologic/neuroimaging evaluations, and the effect of additional somatic genetic events on the hematologic manifestations , it is difficult to estimate the penetrance. However, the majority of persons with a pathogenic variant in SAMD9L will manifest some feature of the syndrome. There is no difference in range of manifestations for males and females. The phenomena of hematopoietic clones with additional genetic alterations repopulating the bone marrow appear to explain striking reports of non-penetrance or spontaneous and long-term disease remission in some affected individuals and some unaffected carrier parents of affected children .

Source: GeneReviews — "SAMD9L Ataxia-Pancytopenia Syndrome"

Diagnostic Criteria

Formal clinical diagnostic criteria for SAMD9L ataxia-pancytopenia (ATXPC) syndrome have not been established.

Suggestive Findings

SAMD9L-ATXPC syndrome should be suspected in individuals with one or more of the following clinical, imaging, and family history findings.

Clinical features

• Cerebellar ataxia

• Variable hematopoietic cytopenias affecting one or more lineages (e.g., anemia, neutropenia, thrombocytopenia)

• Myeloid leukemia or myelodysplasia with partial or complete monosomy 7

Source: GeneReviews — "SAMD9L Ataxia-Pancytopenia Syndrome"

Differential Diagnosis

Hematologic disorders with neurologic manifestations. See .

Table 3.

Disorders to Consider in the Differential Diagnosis of SAMD9L Ataxia-Pancytopenia Syndrome

Gene(s) | Disorder | MOI | Hematologic Manifestations | Neurologic Manifestations | Other

ABCB7

| X-linked sideroblastic anemia ataxia(OMIM 301310) | XL | • Moderate hypochromic microcytic anemia w/o progression to marrow failure

• Not assoc w/malignancy

| Spinocerebellar syndrome in males1 |

ACD

CTC1

DKC1

NHP2

NOP10

PARN

RTEL1

TERC

TERT

TINF2

WRAP53

| Dyskeratosis congenita | XLADAR | • Progressive bone marrow failure

• Myelodysplasia

• Acute myeloid leukemia

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and guide clinical care in an individual diagnosed with SAMD9L ataxia-pancytopenia (ATXPC) syndrome, the evaluations summarized (if not performed as part of the evaluation that led to diagnosis) are recommended.

Table 4.

Recommended Evaluations Following Initial Diagnosis in Individuals with SAMD9L Ataxia-Pancytopenia Syndrome

System/Concern | Evaluation | Comment

Hematologic/

Oncologic

| Complete blood count | To evaluate for anemia, neutropenia, thrombocytopenia, /or myelodysplasia

• Bone marrow exam, incl FISH for chromosome 7

• Consider referral to hematologist/oncologist.

| If hematologic abnormalities are more than minimal

Neurologic

| Assessment by neurologist for:

• Cerebellar motor dysfunction (gait postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades smooth pursuit)

• UMN /or LMN dysfunction (weakness, spasticity, Babinski signs, hyperrefflexia, amyotrophy, fasciculations)

• Vibration loss or polyneuropathy based on clinical findings

| • Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).1

• Consider electrophysiologic studies (EMG NCS) to detect neurogenic changes or signs of neuropathy if sensory or motor abnormalities are detected.

• Brain MRI to evaluate presence severity of cerebellar atrophy

Source: GeneReviews — "SAMD9L Ataxia-Pancytopenia Syndrome"

Clinical Guidance

Nonsteroidal anti-inflammatory agents, anticoagulants, and thrombolytic agents are contraindicated if thrombocytopenia is present and should be used with caution given the fluctuating nature of the cytopenias. Avoid consuming alcohol and medications that cause sedation, which can increase problems with gait and coordination.

Source: GeneReviews — "SAMD9L Ataxia-Pancytopenia Syndrome"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "SAMD9L Ataxia-Pancytopenia Syndrome"

Surveillance Guidelines

Table 6.

Recommended Surveillance for Individuals with SAMD9L Ataxia-Pancytopenia Syndrome

System/Concern | Evaluation | Frequency

Hematologic/

Oncologic

| Complete blood count | At lease annually1

Neurologic

| • Neurologic assessment for progression of ataxia

• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).2

• Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia peripheral neuropathy

| Annually

Dysarthria

| Need for alternative communication method or speech therapy | Per symptom progression

Dysphagia

| Assess aspiration risk feeding methods. | Per symptom progression

BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia

1. More frequent monitoring is required if an affected individual develops signs or symptoms of a cytopenia (e.g., fatigue, pallor, unexpected bleeding, recurrent infections) or if cytopenias are identified.

2.

Source: GeneReviews — "SAMD9L Ataxia-Pancytopenia Syndrome"