Journal of Neuromuscular Diseases 3 (2016) 419–423 419

DOI 10.3233/JND-160171
IOS Press

Short Communication

Stress-Induced Ketoacidosis in Spinal

Muscular Atrophy: An Under-Recognized
Complication
Eoin Mulroy∗ , Sarah Gleeson and Michael James Furlong
Dunedin Public Hospital, Dunedin, New Zealand

Abstract. Ketoacidosis is an important but under-recognized complication of neuromuscular disease, in particular spinal
muscular atrophy. This easily treatable condition is largely overlooked in best practice guidelines, and lack of awareness
contributes to adverse outcomes in this patient population. Neuromyopathy associated ketosis should be considered in all
patients with severe muscle wasting presenting with an elevated anion gap metabolic ketoacidosis. Treatment is simple,
effective, and should be instituted early. Our report of a 50-year-old patient with type 2 spinal muscular atrophy who presents
with recurrent ketoacidosis aims to increase awareness of neuromyopathy associated ketosis as a clinical entity, and to enhance
its early recognition and timely treatment in order to improve patient outcomes.

Keywords: Myopathy, ketosis, acidosis, acid-base equilibrium, muscular atrophy, spinal

INTRODUCTION CASE REPORT

Ketoacidosis is a common cause of metabolic aci-
dosis with elevated anion gap. It is most commonly
encountered in the setting of diabetes, starvation
or alcohol excess. Ketoacidosis is also an under-
recognized complication of neuromuscular diseases
such as spinal muscular atrophy (SMA). In this set-
ting, causative factors include a reduction in muscle
mass, abnormal glucose and fatty acid metabolism,
and possibly changes in endocrine function and
the autonomic nervous system. We report the case
of a 50 year-old man with type 2 spinal muscu-
lar atrophy who presents with recurrent episodes of
stress-induced ketoacidosis.
∗ Correspondence to: Eoin Mulroy, Dunedin Public Hospi-
tal, Great King Street, Dunedin 9016, New Zealand. Tel.:
+64221767127; E-mail: eoinmulroy@gmail.com.
A 50 year-old man with genetically confirmed
spinal muscular atrophy type 2 (homozygous dele-
tion of the SMN1 exon 7 sequence but three copies
on exon 7 and exon 8 of the SMN2 gene) presented to
the emergency department with 1 day of nausea, two
vomits and generalized abdominal discomfort. He
had severe generalized weakness and loss of muscle
mass, required assistance with all activities of daily
living and used a hoist for transfers. His last calcu-
lated BMI in 2003 (10 years prior) was 16.4. Most
of his days were spent in bed. He could not walk but
would feed himself on a soft diet and had adequate
nutritional intake, with an albumin of 36 g/L (normal
35–50 g/L). His cough was poor and he had marked
respiratory muscle weakness with maximum inspi-
ratory pressures of 43% of predicted and maximum
expiratory pressures of 13% of predicted.
Two days prior to presentation, he experienced
dysuria and had been treated with trimethoprim for

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420 E. Mulroy et al. / Ketoacidosis Complicates Neuromuscular Disease
a suspected urinary tract infection (no urine testing
had been performed). Blood testing revealed a severe
metabolic ketoacidosis with mild hypoglycemia (see
Table 1). He was treated with intravenous 50% dex-
trose and started on ceftriaxone for a presumed
partially treated urinary tract infection. By the next
morning, his pH was 7.49 and blood glucose was
normal.
Further history revealed that he had experi-
enced a similar event five years previous where,
following an uncomplicated right external fronto-
ethmoidectomy, routine postoperative blood testing
detected a marked metabolic ketoacidosis and mild
hypoglycemia, which rapidly responded to glucose
supplementation.
DISCUSSION
Spinal Muscular Atrophy (SMA) is a progressive
neurodegenerative disorder caused by deficiency of
the survival motor neuron protein encoded by SMN1
and SMN2 genes on chromosome 5. Without func-
tioning proteins, spinal motor neuron loss, muscle
denervation and loss of muscle mass occur [1]. The
spectrum of SMA is quite broad and is classified
according to the degree of muscle weakness, age of
onset and genetic testing [2]. Ketosis is an important
but under-recognized complication of this neuro-
muscular disease which is often overlooked in best
practice guidelines [3].
Reductions in muscle mass, defects in fatty acid
metabolism, and endocrine changes may all con-
tribute to this predisposition (see Figs. 1 and 2).
We report a case of recurrent severe ketoacidosis
in a patient with SMA, the early recognition and
appropriate treatment of which avoided unneces-
sary over-investigation, inappropriate treatment and
adverse patient outcomes.
Ketoacidosis is an elevated anion gap metabolic
acidosis that results from the accumulation of ketone
bodies (acetoacetate, 3-B-hydroxybutyrate and ace-
tone) in the blood. It is most commonly encountered
in the setting of diabetes, starvation and alcohol
excess. Individuals with spinal muscular atrophy
(SMA) and other patients with severe muscle wasting
are at increased risk for ketoacidosis [4–6].
Ketone bodies are generated in the mitochondria of
liver cells by conversion fatty acids into acetoacetate
and beta-hydroxybutyrate (acetone is generated by
spontaneous decarboxylation of acetoacetate). They
are a vital energy source for the brain, heart and kid-
neys during times of relative glucose scarcity. By day
3 of starvation, ketone bodies provide up to 40% of
the body’s energy needs [7].
When looking at the impact of metabolic path-
ways and glucose handling on the predisposition to
ketosis in SMA patients, an understanding of ketoge-
nesis is paramount. Ketogenesis is tightly regulated
by the balance between the pro-ketotic hormones
glucagon, adrenaline and growth hormone and the
ketone-limiting hormone, insulin. Pro-ketotic hor-
mones increase free fatty acid release from adipose
tissue, whereas insulin reduces the availability of free
fatty acids for ketogenesis [7]. Under conditions of
stress or starvation, a paucity of insulin relative to pro-
ketotic hormones stimulates fatty acid release from
stores. These fatty acid are transported primarily to
the liver where they then undergo beta-oxidation to
form acetyl-CoA [7]. Under normal circumstances,
acetyl-CoA then condenses with oxaloacetate and
enters the citric acid cycle [7], but under hypo-
glycaemic conditions, oxaloacetate gets shunted to
the process of gluconeogenesis. The extra acetyl-
CoA then cannot enter the citric acid cycle and
is instead diverted to ketone body formation (see
Fig. 2).
Episodes of ketoacidosis in SMA patients occur
when several factors converge to create a perfect
storm of metabolic instability. Reductions in muscle
mass, abnormal fatty acid and glucose metabolism,
hormonal imbalance, physiologic stress and auto-
nomic changes may all have a role to play.
Loss of muscle mass favors ketosis in many ways
(see Figs. 1 and 2).
Firstly, skeletal muscle is the primary user of
ketones in the body. A direct effect of less muscle
mass is less ketone body extraction, and therefore
elevated blood ketone levels [8].
Secondly, reduced muscle mass decreases the
availability of amino acids for gluconeogenesis.
Under conditions of stress, those with low muscle
mass (SMA patients and those with other neuromy-
opathies) [8, 9] are predisposed to hypoglycemia,
as was seen in our patient (Table 1). This relative
hypoglycemia promotes ketone body formation both
by shunting oxaloacetate to gluconeogenesis (forcing
acetyl-CoA into ketone body production as described
above) [5, 7, 10], and by making these patients more
dependent on switching to fatty acids as a source
of energy, promoting ketone body formation. In-vivo
experiments have shown that with equal duration of
fasts, myopathic patients develop more ketosis than
normal subjects [8].
 E. Mulroy et al. / Ketoacidosis Complicates Neuromuscular Disease 421

Table 1
Laboratory results from 2009 and 2014. On both occasions, the mild hypoglycemia and ketoacidosis were provoked by an intercurrent stress
(surgery, infection)
Test 2009 2014 Baseline (2014) Normal
pH 7.05 7.09 (7.35–7.45)
pCO2 (mmHg) 23 31 (35–45)
HCO3 (mmol/L) 6.1 8.8 (22–26)
Anion gap (mmol/L) 16.9 27.2 (<12)
Lactate (mmol/L) 0.8 2.2 (0.9–2.2)
Glucose (mmol/L) 3.5 3.3 (3.5–7.7)
(mg/dl) 63 59 (70–100)
Urine Ketones ++++ ++++
Albumin (g/L) 36 35–50
Haemoglobin A1c (mmol/mol) 30 20–40
Na (mmol/L) 141 137 141 (135–145)
K (mmol/L) 4.9 4.9 5.5 (3.5–5.2)
Chloride (mmol/L) 118 101 (96–106)
Urea (mmol/L) 5.8 7.5 (2.6–6.8)
(mg/dl) 16 21 (8–20)
Creatinine(␮mol/L) 22 36 <24 (50–110)
(mg/dl) 0.24 0.41 <0.27 (0.7–1.3)

INSULIN

GROWTH HORMONE,
ADRENALINE, GLUCAGON

FATTY ACID GLUCOSE

Acetyl-CoA OXALOACETATE

hepatic
mitochondria
Amino Acids

normal muscle mass

ketone bodies

Fig. 1. Ketone metabolism in patients with normal muscle mass. In patients with normal muscle mass, there is a readily available pool of
stored amino acids to act as substrates for gluconeogenesis. This allows glucose levels to be maintained and avoid the need for ketogenesis.
Oxaloacetate is plentiful and can readily condense with acetyl-CoA and allow it to enter the citric acid cycle. Any formed ketone bodies
can be used by the large muscle mass (and other tissues e.g.brain). [This work is a modification of the somersault1824.com free online
illustrations licensed under CC BY-NC-SA 4.0].

Defects in fatty acid metabolism may also ren- state develop a distinctive and marked dicarboxylic
der SMA patients prone to ketosis [4, 11, 12]. aciduria, comparable in severity to that seen in chil-
Infants with severe SMA evaluated in a fasting dren with primary defects of beta-oxidation [4]. It
422 E. Mulroy et al. / Ketoacidosis Complicates Neuromuscular Disease

INSULIN

GROWTH HORMONE,
ADRENALINE, GLUCAGON

FATTY ACID GLUCOSE

Acetyl-CoA OXALOACETATE

hepatic
mitochondria
Amino Acids

ketone bodies

Reduced Muscle Mass

(decreased potential for
ketone clearance)

Fig. 2. Ketone metabolism in neuromyopathic patients. Under conditions of reduced muscle mass, less amino acid precursors are available
for gluconeogenesis. This predisposes to hypoglycemia. In response, lipoprotein lipase is activated and releases fatty acids from adipose
stores. Reduced availability of oxaloacetate means that acetyl-CoA gets shifted towards ketone body production rather that entering the
citric acid cycle. The amount of ketone bodies taken up by muscle is also reduced because of the reduced muscle mass. [This work is a
modification of the somersault1824.com free online illustrations licensed under CC BY-NC-SA 4.0].

is postulated that the observed defects in fatty acid
metabolism in SMA may relate to changes in cellular
physiology resulting from absence of the SMN gene
product, defects in neighboring genes or the absence
of a neural ‘trophic factor’ [13, 14].
Hormonal changes in SMA also predispose to keto-
sis. As previously discussed, the insulin:glucagon
ratio is a critical regular of ketone body forma-
tion. Interestingly, both human and animal models
of pancreatic islet constituents in SMA demonstrate
progressive loss of insulin-producing beta cells as
the disease progresses [15]. The resulting increase
in alpha (glucagon producing):beta cell ratio favors
ketosis.
There is increasing recognition of the importance
of the autonomic nervous systemic in the control of
hepatic metabolic functions [16, 17]. Patients with
SMA have recently been found to have problems
with autonomic regulation [18]. More work is needed
to determine whether autonomic dysregulation con-
tributes to ketosis in SMA patients [19].
Once diagnosed, ‘neuromyopathic’ ketosis is eas-
ily treated, requiring only carbohydrate replacement
and avoidance of hypoglycemia. This reverses the
body’s drive towards ketosis and will restore pH and
serum ketones to normal levels within hours to days.
Intercurrent illness must also be sought and appropri-
ately managed.
In conclusion, although the main manifestations
SMA are neuromyopathic in nature, these individuals
are also at increased risk of developing ketoacido-
sis. Reductions in muscle mass, alterations in fatty
acid metabolism and endocrine imbalance all provide
stimuli to ketosis, especially during times of stress.
Ketoacidosis in spinal muscular atrophy patients is
simply treated with enteral or parenteral glucose.
 E. Mulroy et al. / Ketoacidosis Complicates Neuromuscular Disease
Early recognition and treatment of ketoacidosis cor-
rects metabolic parameters within hours to days,
improving patient outcomes.
CONFLICT OF INTEREST
The authors have no conflict of interest to report.
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